16p11.2 Copy Number Variations and Neurodevelopmental Disorders

May combine two claims.

Motor delays are reported at rates of 57.1% and 50% in 16p11.2 deletion carriers, and in 60% of duplication carriers.

“Motor delays are reported at rates of 57.1% [15] and 50% [17] in deletion carriers, and in 60% of duplication carriers [17].”

• cites [15] Hanson E,, Cognitive and behavioral characterization of 16p11.2 deletion syndrome. Journal of Developmental & Behavioral Pediatrics, 2010 31: p. 649– 657. 20613623 sourceNot checked yet

  Not checked in the free run.

• cites [17] Shinawi M,, Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. Journal of Medical Genetics, 2010 47(5): p. 332– 341. 19914906 PMC3158566 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In multiple studies, autistic features or a formal ASD diagnosis were reported in 16.1%-25.6% of 16p11.2 deletion carriers and 20%-33.9% of duplication carriers.

“In multiple studies of subjects with 16p11.2 deletion or duplication, autistic features or a formal ASD diagnosis were reported in 16.1% - 25.6% of deletion carriers, and 20% - 33.9% of duplication carriers.”

May combine two claims.

In individuals with neurodevelopmental disorders, genetic screenings find 16p11.2 deletions at rates of 0.25-2.9% and duplications at rates of 0.15-0.78%.

“Data compiled from eight studies [13, 15–17, 20, 24, 26, 33] screening individuals with either ASD, ID, developmental delay (DD), dysmorphic features (DF), multiple congenital anomalies (MCA), obesity, or seizures find 16p11.2 deletions at rates of 0.25–2.9%, and duplications at rates between 0.15–0.78% (Table 1).”

• cites [13] Weiss LA,, Association between microdeletion and microduplication at 16p11.2 and autism. The New England Journal of Medicine, 2008 358: p. 667– 675. 18184952 sourceNot checked yet

  Not checked in the free run.

• cites [15] Hanson E,, Cognitive and behavioral characterization of 16p11.2 deletion syndrome. Journal of Developmental & Behavioral Pediatrics, 2010 31: p. 649– 657. 20613623 sourceNot checked yet

  Not checked in the free run.

• cites [16] Rosenfeld JA,, Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications. Journal of Neurodevelopmental Disorders, 2010 2: p. 26– 38. 21731881 PMC3125720 sourceNot checked yet

  Not checked in the free run.

• cites [17] Shinawi M,, Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. Journal of Medical Genetics, 2010 47(5): p. 332– 341. 19914906 PMC3158566 sourceNot checked yet

  Not checked in the free run.

• cites [20] Walters RG,, A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature, 2010 463(7281): p. 671– 5. 20130649 PMC2880448 sourceNot checked yet

  Not checked in the free run.

• cites [24] Jacquemont S,, Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature, 2011 478(7367): p. 97– 102. 21881559 PMC3637175 sourceNot checked yet

  Not checked in the free run.

• cites [26] Sahoo T,, Copy number variants of schizophrenia susceptibility loci are associated with a spectrum of speech and developmental delays and behavior problems. Genet Med, 2011 13(10): p. 868– 80. 21792059 sourceNot checked yet

  Not checked in the free run.

• cites [33] Bijlsma EK,, Extending the phenotype of current rearrangements of 16p11.2: deletions in mentally retarded patients without autism and in normal individuals. European Journal of Medical Genetics, 2009 52: p. 77– 87. 19306953 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Developmental coordination disorder is reported at rates of 32% and 57.7% in 16p11.2 deletion carriers, and 46.8% in duplication carriers.

“Developmental coordination disorder is reported at rates of 32% [23] and 57.7% [21] in deletion carriers, and 46.8% in duplication carriers [19].”

• cites [23] Qureshi AY,, Opposing brain differences in 16p11.2 deletion and duplication carriers. J Neurosci, 2014 34(34): p. 11199– 211. 25143601 PMC4138332 sourceNot checked yet

  Not checked in the free run.

• cites [21] Hanson E,, The cognitive and behavioral phenotype of the 16p11.2 deletion in a clinically ascertained population. Biological Psychiatry, 2015 77: p. 785– 793. 25064419 PMC5410712 sourceNot checked yet

  Not checked in the free run.

• cites [19] Green Snyder L,, Autism Spectrum Disorder, Developmental and Psychiatric Features in 16p11.2 Duplication. J Autism Dev Disord, 2016 46(8): p. 2734– 48. 27207092 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In studies with at least 50 subjects, 60-76% of 16p11.2 deletions were reported as de novo, while only 16-29% of 16p11.2 duplications occurred de novo.

“In studies with at least 50 subjects, between 60–76% of 16p11.2 deletions were reported as de novo events [10, 12, 34, 36], while only 16–29% of 16p11.2 duplications occurred de novo [10, 19, 34, 36].”

• cites [10] D'Angelo D,, Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities. JAMA Psychiatry, 2016 73(1): p. 20– 30. 26629640 PMC5894477 sourceNot checked yet

  Not checked in the free run.

• cites [12] Zufferey F,, A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. Journal of Medical Genetics, 2012 49: p. 660– 668. 23054248 PMC3494011 sourceNot checked yet

  Not checked in the free run.

• cites [34] Niarchou M,, Psychiatric disorders in children with 16p11.2 deletion and duplication. Transl Psychiatry, 2019 9(1): p. 8. 30664628 PMC6341088 sourceNot checked yet

  Not checked in the free run.

• cites [36] Steinman KJ,, 16p11.2 deletion and duplication: Characterizing neurologic phenotypes in a large clinically ascertained cohort. Am J Med Genet A, 2016 170(11): p. 2943– 2955. 27410714 sourceNot checked yet

  Not checked in the free run.

• cites [19] Green Snyder L,, Autism Spectrum Disorder, Developmental and Psychiatric Features in 16p11.2 Duplication. J Autism Dev Disord, 2016 46(8): p. 2734– 48. 27207092 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In one group of 16p11.2 duplication carriers, FSIQ scores ranged from 33 to 129, with 17% showing severe impairment (<55) and 33% falling within the average range or better.

“In one group of 16p11.2 duplication carriers, FSIQ scores range from 33–129, with 17% displaying severe impairment (<55), while 33% fall within the average range or better [19].”

• cites [19] Green Snyder L,, Autism Spectrum Disorder, Developmental and Psychiatric Features in 16p11.2 Duplication. J Autism Dev Disord, 2016 46(8): p. 2734– 48. 27207092 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In the general population, 16p11.2 deletions have been reported at rates of 0.028%-0.043%, and duplications at 0.035%-0.053%.

“16p11.2 deletions have been reported at rates of 0.028% - 0.043% in the general population, while duplications have been reported between 0.035% - 0.053% (Table 1).”

May combine two claims.

In studies of at least 50 subjects, ID was reported in 10.3%-28.1% of 16p11.2 deletion carriers and 30.5%-40.3% of duplication carriers.

“In studies of at least 50 subjects, ID was reported in 10.3% - 28.1% of 16p11.2 deletion carriers, and 30.5% - 40.3% of duplication carriers.”

May combine two claims.

Both 16p11.2 deletions and duplications appear to be preferentially maternally inherited.

“Both the deletion and duplication appear to be preferentially maternally inherited.”

May combine two claims.

In studies of at least 50 subjects, epilepsy/seizures has been reported in 21.8%-26.8% of 16p11.2 deletion carriers and 19.4%-29% of duplication carriers.

“In studies of at least 50 subjects, epilepsy/seizures has been reported in 21.8% - 26.8% of deletion carriers, and 19.4% - 29% of duplication carriers.”

May combine two claims.

Psychotic symptoms have been reported in 6.1% of 16p11.2 duplication carriers and 2.3% of deletion carriers.

“Psychotic symptoms have also been reported in duplication (7/114 [6.1%]) and deletion (5/217 [2.3%]) carriers [34].”

• cites [34] Niarchou M,, Psychiatric disorders in children with 16p11.2 deletion and duplication. Transl Psychiatry, 2019 9(1): p. 8. 30664628 PMC6341088 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In studies of at least 50 subjects, macrocephaly was reported in 17.1%-17.3% of 16p11.2 deletion carriers, while microcephaly was reported in 17.1%-22.3% of duplication carriers.

“In studies of at least 50 subjects, macrocephaly was reported in 17.1% - 17.3% of deletion carriers, while microcephaly was reported in 17.1% - 22.3% of duplication carriers.”

May combine two claims.

In one study, both 16p11.2 deletion and duplication carriers exhibited psychotic symptoms, though only duplication was a significant predictor of psychotic symptoms.

“In one study, both 16p11.2 deletion and duplication carriers exhibited psychotic symptoms, though only the duplication was a significant predictor of psychotic symptoms [44].”

• cites [44] Jutla A,, Psychotic symptoms in 16p11.2 copy-number variant carriers. Autism Res, 2020 13(2): p. 187– 198. 31724820 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In studies of at least 50 subjects, dysmorphic features/congenital anomalies were reported in 21.1%-58.5% of 16p11.2 deletion carriers and 16.7%-28.7% of duplication carriers, indicating high penetrance in both CNVs.

“In studies of at least 50 subjects, DF/CA were reported in in 21.1% - 58.5% of deletion carriers, and 16.7% - 28.7% of duplication carriers, indicating high penetrance in both CNVs.”

May combine two claims.

Birth parameters for 16p11.2 duplication carriers are generally normal, indicating a postnatal effect.

“Birth parameters for 16p11.2 duplication carriers are generally normal [24], indicating a postnatal effect.”

• cites [24] Jacquemont S,, Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature, 2011 478(7367): p. 97– 102. 21881559 PMC3637175 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

An analysis of 22 screenings found 98 duplications in 36,676 SZ patients (0.26%) and only 12 duplications in 48,331 controls (0.025%), indicating a 10.79-fold increase in SZ risk.

“An analysis of 22 screenings in various populations found 98 duplications in 36,676 SZ patients (0.26%), with only 12 duplications in 48,331 controls (0.025%), indicating a 10.79-fold increase in risk for developing SZ [43].”

• cites [43] Chang H,, Rare and common variants at 16p11.2 are associated with schizophrenia. Schizophr Res, 2017 184: p. 105– 108. 27889382 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

ADHD is observed in 16p11.2 CNV carriers at rates as high as 29% (63/217) in deletion carriers and 42% (48/114) in duplication carriers.

“Attention-deficit/hyperactivity disorder (ADHD) is also observed in 16p11.2 CNV carriers [12, 15–17, 19, 23, 48], at rates as high as 29% (63/217) and 42% (48/114) in deletion and duplication carriers, respectively [34].”

• cites [12] Zufferey F,, A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. Journal of Medical Genetics, 2012 49: p. 660– 668. 23054248 PMC3494011 sourceNot checked yet

  Not checked in the free run.

• cites [15] Hanson E,, Cognitive and behavioral characterization of 16p11.2 deletion syndrome. Journal of Developmental & Behavioral Pediatrics, 2010 31: p. 649– 657. 20613623 sourceNot checked yet

  Not checked in the free run.

• cites [16] Rosenfeld JA,, Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications. Journal of Neurodevelopmental Disorders, 2010 2: p. 26– 38. 21731881 PMC3125720 sourceNot checked yet

  Not checked in the free run.

• cites [17] Shinawi M,, Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. Journal of Medical Genetics, 2010 47(5): p. 332– 341. 19914906 PMC3158566 sourceNot checked yet

  Not checked in the free run.

• cites [19] Green Snyder L,, Autism Spectrum Disorder, Developmental and Psychiatric Features in 16p11.2 Duplication. J Autism Dev Disord, 2016 46(8): p. 2734– 48. 27207092 sourceNot checked yet

  Not checked in the free run.

• cites [23] Qureshi AY,, Opposing brain differences in 16p11.2 deletion and duplication carriers. J Neurosci, 2014 34(34): p. 11199– 211. 25143601 PMC4138332 sourceNot checked yet

  Not checked in the free run.

• cites [48] Gudmundsson OO,, Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder. Transl Psychiatry, 2019 9(1): p. 258. 31624239 PMC6797719 sourceNot checked yet

  Not checked in the free run.

• cites [34] Niarchou M,, Psychiatric disorders in children with 16p11.2 deletion and duplication. Transl Psychiatry, 2019 9(1): p. 8. 30664628 PMC6341088 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In a 2009 study, 21 duplications and 1 deletion were detected among 5,877 schizophrenia patients, indicating a 14.5-fold increased SZ risk in 16p11.2 duplication patients.

“In a 2009 study, 21 duplications and 1 deletion were detected among 5,877 schizophrenia (SZ) patients, indicating a 14.5-fold increased SZ risk in 16p11.2 duplication patients [9].”

• cites [9] McCarthy SE,, Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet, 2009 41(11): p. 1223– 7. 19855392 PMC2951180 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Male 16p11.2+/− mice (Mills) exhibit sleep deficits and impairments in a reward-directed learning task, while females do not.

“Additionally, male 16p11.2+/− mice (Mills) exhibit sleep deficits [70], and impairments in a reward-directed learning task [67], while females do not.”

• cites [70] Angelakos CC,, Hyperactivity and male-specific sleep deficits in the 16p11.2 deletion mouse model of autism. Autism Research, 2017 10: p. 572– 584. 27739237 PMC6201314 sourceNot checked yet

  Not checked in the free run.

• cites [67] Grissom NM,, Male-specific deficits in natural reward learning in a mouse model of neurodevelopmental disorders. Mol Psychiatry, 2017 23: p. 544– 555. 29038598 PMC5822461 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Mild motor deficits are present in 16p11.2+/− models, consistent with human phenotypes.

“Mild motor deficits are also present in these models [4, 61, 68], consistent with human phenotypes.”

• cites [4] Portmann T,, Behavioral abnormalities and circuit defects in the basal ganglia of a mouse model of 16p11.2 deletion syndrome. Cell Reports, 2014 7: p. 1077– 1092. 24794428 PMC4251471 sourceNot checked yet

  Not checked in the free run.

• cites [61] Brunner D,, Comprehensive Analysis of the 16p11.2 Deletion and Null Cntnap2 Mouse Models of Autism Spectrum Disorder. PLoS One, 2015 10(8): p. e0134572. 26273832 PMC4537259 sourceNot checked yet

  Not checked in the free run.

• cites [68] Yang M,, 16p11.2 deletion mice display cognitive deficits in touchscreen learning and novelty recognition tasks. Learning and Memory, 2015 22(12): p. 622– 632. 26572653 PMC4749736 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Hyperlocomotion is broadly reported in 16p11.2+/− mice, another behavioral feature that does not coincide directly with human symptomology.

“Hyperlocomotion is also broadly reported in 16p11.2+/− mice [4, 5, 59, 61, 63, 64, 70], another behavioral feature that does not coincide directly with human symptomology.”

• cites [4] Portmann T,, Behavioral abnormalities and circuit defects in the basal ganglia of a mouse model of 16p11.2 deletion syndrome. Cell Reports, 2014 7: p. 1077– 1092. 24794428 PMC4251471 sourceNot checked yet

  Not checked in the free run.

• cites [5] Horev G,, Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism. PNAS, 2011 108(41): p. 17076– 17081. 21969575 PMC3193230 sourceNot checked yet

  Not checked in the free run.

• cites [59] Arbogast T,, Reciprocal Effects on Neurocognitive and Metabolic Phenotypes in Mouse Models of 16p11.2 Deletion and Duplication Syndromes. PLoS Genet, 2016 12(2): p. e1005709. 26872257 PMC4752317 sourceNot checked yet

  Not checked in the free run.

• cites [61] Brunner D,, Comprehensive Analysis of the 16p11.2 Deletion and Null Cntnap2 Mouse Models of Autism Spectrum Disorder. PLoS One, 2015 10(8): p. e0134572. 26273832 PMC4537259 sourceNot checked yet

  Not checked in the free run.

• cites [63] Yang M,, In tribute to Bob Blanchard: Divergent behavioral phenotypes of 16p11.2 deletion mice reared in same-genotype versus mixed-genotype cages. Physiol Behav, 2015 146: p. 16– 27. 26066718 sourceNot checked yet

  Not checked in the free run.

• cites [64] Stoppel LJ,, R-Baclofen Reverses Cognitive Deficits and Improves Social Interactions in Two Lines of 16p11.2 Deletion Mice. Neuropsychopharmacology, 2018 43(3): p. 513– 524. 28984295 PMC5770771 sourceNot checked yet

  Not checked in the free run.

• cites [70] Angelakos CC,, Hyperactivity and male-specific sleep deficits in the 16p11.2 deletion mouse model of autism. Autism Research, 2017 10: p. 572– 584. 27739237 PMC6201314 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

16p11.2dp/+ mice (Mills) exhibit social and cognitive deficits along with increased repetitive self-grooming, with the absence of motor coordination deficits.

“The 16p11.2dp/+ mice (Mills) exhibit social and cognitive deficits [72, 73] along with increased repetitive self-grooming [5, 72], with the absence of motor coordination deficits [72].”

• cites [72] Rein B,, Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4. Mol Psychiatry, 2020(Epub ahead of print). PMC7483162 32099100 sourceNot checked yet

  Not checked in the free run.

• cites [73] Bristow GC,, 16p11 Duplication Disrupts Hippocampal-Orbitofrontal-Amygdala Connectivity, Revealing a Neural Circuit Endophenotype for Schizophrenia. Cell Rep, 2020 31(3): p. 107536. 32320645 sourceNot checked yet

  Not checked in the free run.

• cites [5] Horev G,, Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism. PNAS, 2011 108(41): p. 17076– 17081. 21969575 PMC3193230 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Two behavioral phenotypes associated with SZ, PPI of startle responses and MK-801-induced hyperlocomotion, were not observed in 16p11.2dp/+ mice, despite a report on female-specific PPI deficits.

“Two behavioral phenotypes associated with SZ, PPI of startle responses and MK-801-induced hyperlocomotion, were not observed in 16p11.2dp/+ mice [72], despite a report on female-specific PPI deficits [73].”

• cites [72] Rein B,, Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4. Mol Psychiatry, 2020(Epub ahead of print). PMC7483162 32099100 sourceNot checked yet

  Not checked in the free run.

• cites [73] Bristow GC,, 16p11 Duplication Disrupts Hippocampal-Orbitofrontal-Amygdala Connectivity, Revealing a Neural Circuit Endophenotype for Schizophrenia. Cell Rep, 2020 31(3): p. 107536. 32320645 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

16p11.2+/− mice (Mills) display deficient NMDA-receptor-mediated glutamatergic transmission and reduced action potential firing frequency in mPFC pyramidal neurons, along with increased excitation-inhibition ratio in somatosensory cortex.

“The 16p11.2+/− mice (Mills) display deficient NMDA-receptor-mediated glutamatergic transmission and reduced frequency of action potential firing in medial prefrontal cortex (mPFC) pyramidal neurons [62], along with increased excitation-inhibition (E-I) ratio in somatosensory cortex [75].”

• cites [62] Wang W,, Chemogenetic Activation of Prefrontal Cortex Rescues Synaptic and Behavioral Deficits in a Mouse Model of 16p11.2 Deletion Syndrome. J Neurosci, 2018 38(26): p. 5939– 5948. 29853627 PMC6021990 sourceNot checked yet

  Not checked in the free run.

• cites [75] Antoine MW,, Increased Excitation-Inhibition Ratio Stabilizes Synapse and Circuit Excitability in Four Autism Mouse Models. Neuron, 2019 101(4): p. 648– 661 e4. 30679017 PMC6733271 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

All three lines of 16p11.2+/− mice display social deficits in various testing paradigms and an array of cognitive deficits.

“All 3 lines of 16p11.2+/− mice display social deficits in various testing paradigms [59–64], and an array of cognitive deficits [4, 59, 62–68].”

• cites [59] Arbogast T,, Reciprocal Effects on Neurocognitive and Metabolic Phenotypes in Mouse Models of 16p11.2 Deletion and Duplication Syndromes. PLoS Genet, 2016 12(2): p. e1005709. 26872257 PMC4752317 sourceNot checked yet

  Not checked in the free run.

• cites [60] Yang M,, 16p11.2 deletion syndrome mice display sensory and ultrasonic vocalization deficits during social interactions. Autism Research, 2015 8(5): p. 507– 521. 25663600 PMC5321681 sourceNot checked yet

  Not checked in the free run.

• cites [61] Brunner D,, Comprehensive Analysis of the 16p11.2 Deletion and Null Cntnap2 Mouse Models of Autism Spectrum Disorder. PLoS One, 2015 10(8): p. e0134572. 26273832 PMC4537259 sourceNot checked yet

  Not checked in the free run.

• cites [62] Wang W,, Chemogenetic Activation of Prefrontal Cortex Rescues Synaptic and Behavioral Deficits in a Mouse Model of 16p11.2 Deletion Syndrome. J Neurosci, 2018 38(26): p. 5939– 5948. 29853627 PMC6021990 sourceNot checked yet

  Not checked in the free run.

• cites [63] Yang M,, In tribute to Bob Blanchard: Divergent behavioral phenotypes of 16p11.2 deletion mice reared in same-genotype versus mixed-genotype cages. Physiol Behav, 2015 146: p. 16– 27. 26066718 sourceNot checked yet

  Not checked in the free run.

• cites [64] Stoppel LJ,, R-Baclofen Reverses Cognitive Deficits and Improves Social Interactions in Two Lines of 16p11.2 Deletion Mice. Neuropsychopharmacology, 2018 43(3): p. 513– 524. 28984295 PMC5770771 sourceNot checked yet

  Not checked in the free run.

• cites [4] Portmann T,, Behavioral abnormalities and circuit defects in the basal ganglia of a mouse model of 16p11.2 deletion syndrome. Cell Reports, 2014 7: p. 1077– 1092. 24794428 PMC4251471 sourceNot checked yet

  Not checked in the free run.

• cites [65] Tian D,, Contribution of mGluR5 to hippocampal pathophysiology in a mouse model of human chromosome 16p11.2 microdeletion. Nature Neuroscience, 2015 18(2): p. 182– 184. 25581360 PMC4323380 sourceNot checked yet

  Not checked in the free run.

• cites [66] Pucilowska J,, The 16p11.2 deletion mouse model of autism exhibits altered cortical progenitor proliferation and brain cytoarchitecture linked to the ERK MAPK pathway. J Neurosci, 2015 35(7): p. 3190– 200. 25698753 PMC6605601 sourceNot checked yet

  Not checked in the free run.

• cites [67] Grissom NM,, Male-specific deficits in natural reward learning in a mouse model of neurodevelopmental disorders. Mol Psychiatry, 2017 23: p. 544– 555. 29038598 PMC5822461 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Hypolocomotion and enhanced object recognition memory are reported in 16p11.2dp/+ mice (Herault) on a C57BL/6N inbred background, whereas on a F1 C57BL/6N-C3B hybrid background, mice additionally exhibit social approach deficits.

“Hypolocomotion and enhanced object recognition memory are reported in 16p11.2dp/+ mice (Herault) on a C57BL/6N inbred genetic background, whereas on a F1 C57BL/6N-C3B hybrid background, mice additionally exhibit social approach deficits [59].”

• cites [59] Arbogast T,, Reciprocal Effects on Neurocognitive and Metabolic Phenotypes in Mouse Models of 16p11.2 Deletion and Duplication Syndromes. PLoS Genet, 2016 12(2): p. e1005709. 26872257 PMC4752317 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Startle response and pre-pulse inhibition are severely impaired in the 16p11.2+/− mice (Dolmetsch).

“Startle response [4, 60] and pre-pulse inhibition (PPI) [60] are severely impaired in the 16p11.2+/− mice (Dolmetsch).”

• cites [4] Portmann T,, Behavioral abnormalities and circuit defects in the basal ganglia of a mouse model of 16p11.2 deletion syndrome. Cell Reports, 2014 7: p. 1077– 1092. 24794428 PMC4251471 sourceNot checked yet

  Not checked in the free run.

• cites [60] Yang M,, 16p11.2 deletion syndrome mice display sensory and ultrasonic vocalization deficits during social interactions. Autism Research, 2015 8(5): p. 507– 521. 25663600 PMC5321681 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Cultured pyramidal neurons from 16p11.2dp/+ mice exhibit increased ERK1 phosphorylation and greater dendritic arborization, which can be reversed by ERK inhibition.

“Cultured pyramidal neurons from 16p11.2dp/+ mice exhibit increased ERK1 phosphorylation, and greater dendritic arborization, which can be reversed by ERK inhibition [81].”

• cites [81] Blizinsky KD,, Reversal of dendritic phenotypes in 16p11.2 microduplication mouse model neurons by pharmacological targeting of a network hub. Proc Natl Acad Sci U S A, 2016 113(30): p. 8520– 5. 27402753 PMC4968749 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

GABAergic neurons in the ventral medulla of 16p11.2+/− mice display hyperpolarized resting membrane potential and increased membrane resistance.

“Additionally, GABAergic neurons in the ventral medulla display hyperpolarized resting membrane potential and increased membrane resistance [69].”

• cites [69] Lu HC,, Altered sleep architecture, rapid eye movement sleep, and neural oscillation in a mouse model of human chromosome 16p11.2 microdeletion. Sleep, 2019 42(3). PMC7850008 30541142 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

NAc medium spiny neurons in 16p11.2+/− mice (Dolmetsch) display increased AMPAR/NMDAR ratio and decreased paired pulse ratios, along with increased miniature EPSC frequency.

“Nucleus accumbens (NAc) medium spiny neurons (MSNs) in 16p11.2+/− mice (Dolmetsch) display increased AMPAR/NMDAR ratio and decreased paired pulse ratios (PPR), along with increased miniature EPSC frequency [4].”

• cites [4] Portmann T,, Behavioral abnormalities and circuit defects in the basal ganglia of a mouse model of 16p11.2 deletion syndrome. Cell Reports, 2014 7: p. 1077– 1092. 24794428 PMC4251471 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

GO analysis indicates that the largest portion of downregulated genes are classified as transcription factors (17.7%), consistent with prior RNA-seq data.

“GO analysis indicates that the largest portion of downregulated genes are classified as “Transcription Factors” (17.7%), consistent with prior RNA-seq data [76].”

• cites [76] Blumenthal I,, Transcriptional consequences of 16p11.2 deletion and duplication in mouse cortex and multiplex autism families. Am J Hum Genet, 2014 94(6): p. 870– 83. 24906019 PMC4121471 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Human iPSC-derived neurons from 16p11.2 deletion/duplication carriers display increased soma size/dendrite length in deletion neurons and reduced size/dendrite length in duplication neurons.

“Human induced pluripotent stem cell (iPSC)-derived neurons from 16p11.2 deletion/duplication carriers display corresponding features, with increased soma size/dendrite length in 16p11.2 deletion neurons, and reduced size/dendrite length in duplication neurons [77].”

• cites [77] Deshpande A,, Cellular Phenotypes in Human iPSC-Derived Neurons from a Genetic Model of Autism Spectrum Disorder. Cell Rep, 2017 21(10): p. 2678– 2687. 29212016 PMC5730067 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In humans, mutations in MAPK3 and TAOK2 but not in KCTD13 have been found in ASD cases.

“In humans, mutations in MAPK3 [92] and TAOK2 [93, 94] but not in KCTD13 [85, 95] have been found in ASD cases.”

• cites [92] Schaaf CP,, Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders. Hum Mol Genet, 2011 20(17): p. 3366– 75. 21624971 PMC3153303 sourceNot checked yet

  Not checked in the free run.

• cites [93] Lim ET,, Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Nat Neurosci, 2017 20(9): p. 1217– 1224. 28714951 PMC5672813 sourceNot checked yet

  Not checked in the free run.

• cites [94] RK CY,, Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. Nat Neurosci, 2017 20(4): p. 602– 611. 28263302 PMC5501701 sourceNot checked yet

  Not checked in the free run.

• cites [85] DeRubeis S,, Synaptic, transcriptional and chromatin genes disrupted in autism. Nature, 2014 515(7526): p. 209– 15. 25363760 PMC4402723 sourceNot checked yet

  Not checked in the free run.

• cites [95] Satterstrom FK,, Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism. Cell, 2020 180(3): p. 568– 584 e23. 31981491 PMC7250485 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In zebrafish, out of all 16p11.2 gene transcripts, only KCTD13 overexpression drives a microcephalic phenotype with reduced brain cell counts, whereas its suppression produces a macrocephalic phenotype with increased brain cell counts.

“In zebrafish, out of all 16p11.2 gene transcripts, only KCTD13 overexpression drives a microcephalic phenotype with reduced brain cell counts, whereas its suppression produces a macrocephalic phenotype with increased brain cell counts [6].”

• cites [6] Golzio C,, KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. Nature, 2012 485(7398): p. 363– 7. 22596160 PMC3366115 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

LTP/LTD appear intact in hippocampal CA1 of 16p11.2+/− mice (Mills), though protein-synthesis-dependent mGluR5 LTD is impaired.

“Long term potentiation and depression (LTP/LTD) appear to be intact in hippocampal CA1 of 16p11.2+/− mice (Mills), though protein-synthesis-dependent mGluR5 LTD is impaired [65].”

• cites [65] Tian D,, Contribution of mGluR5 to hippocampal pathophysiology in a mouse model of human chromosome 16p11.2 microdeletion. Nature Neuroscience, 2015 18(2): p. 182– 184. 25581360 PMC4323380 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

LoF variants in TAOK2 are identified in ASD probands, however it is not a top-ranking ASD risk factor by large genetic screening.

“LoF variants in TAOK2 are identified in ASD probands [93, 94], however it is not a top-ranking ASD risk factor by large genetic screening [85].”

• cites [93] Lim ET,, Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Nat Neurosci, 2017 20(9): p. 1217– 1224. 28714951 PMC5672813 sourceNot checked yet

  Not checked in the free run.

• cites [94] RK CY,, Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. Nat Neurosci, 2017 20(4): p. 602– 611. 28263302 PMC5501701 sourceNot checked yet

  Not checked in the free run.

• cites [85] DeRubeis S,, Synaptic, transcriptional and chromatin genes disrupted in autism. Nature, 2014 515(7526): p. 209– 15. 25363760 PMC4402723 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Disrupted connectivity between hippocampal-orbitofrontal and hippocampal-amygdala circuits has been found in 16p11.2dp/+ mice (Mills), as well as reduced expression of several GABAergic markers, including parvalbumin, calbindin and somatostatin in frontal cortex.

“In addition, disrupted connectivity between hippocampal-orbitofrontal and hippocampal-amygdala circuits has been found in 16p11.2dp/+ mice (Mills), as well as reduced expression of several GABAergic markers, including parvalbumin, calbindin and somatostatin in frontal cortex [73].”

• cites [73] Bristow GC,, 16p11 Duplication Disrupts Hippocampal-Orbitofrontal-Amygdala Connectivity, Revealing a Neural Circuit Endophenotype for Schizophrenia. Cell Rep, 2020 31(3): p. 107536. 32320645 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Restoring mPFC GABAergic synaptic activity is sufficient to reverse the social and cognitive deficits in 16p11.2dp/+ mice, implicating prefrontal cortical synaptic dysfunction in 16p11.2 duplication pathology.

“Restoring mPFC GABAergic synaptic activity is sufficient to reverse the social and cognitive deficits [72], implicating prefrontal cortical synaptic dysfunction in 16p11.2 duplication pathology.”

• cites [72] Rein B,, Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4. Mol Psychiatry, 2020(Epub ahead of print). PMC7483162 32099100 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Missense variants in MAPK3 are identified in ASD probands, but no loss of function MAPK3 mutations have been reported in ASD, leaving the direct link to ASD uncertain.

“Missense variants in MAPK3 are identified in ASD probands [85, 92], but no loss of function (LoF) MAPK3 mutations have been reported in ASD, leaving the direct link to ASD uncertain.”

• cites [85] DeRubeis S,, Synaptic, transcriptional and chromatin genes disrupted in autism. Nature, 2014 515(7526): p. 209– 15. 25363760 PMC4402723 sourceNot checked yet

  Not checked in the free run.

• cites [92] Schaaf CP,, Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders. Hum Mol Genet, 2011 20(17): p. 3366– 75. 21624971 PMC3153303 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

16p11.2+/− mice display reduced brain size and reductions in upper layer cortical projection neurons, driven by increased progenitor proliferation and premature cell cycle exit, resulting in depleted progenitor pools and maldeveloped cortical structures.

“In contrast, 16p11.2+/− mice display reduced brain size and reductions in upper layer cortical projection neurons, driven by increased progenitor proliferation and premature cell cycle exit, resulting in depleted progenitor pools and maldeveloped cortical structures [66].”

• cites [66] Pucilowska J,, The 16p11.2 deletion mouse model of autism exhibits altered cortical progenitor proliferation and brain cytoarchitecture linked to the ERK MAPK pathway. J Neurosci, 2015 35(7): p. 3190– 200. 25698753 PMC6605601 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

An elevated number of MSNs and increased expression of Drd2 in striatum are found in male 16p11.2+/− mice (Mills).

“An elevated number of MSNs and the increased expression of Drd2 in striatum are found in male 16p11.2+/− mice (Mills) [4, 67].”

• cites [4] Portmann T,, Behavioral abnormalities and circuit defects in the basal ganglia of a mouse model of 16p11.2 deletion syndrome. Cell Reports, 2014 7: p. 1077– 1092. 24794428 PMC4251471 sourceNot checked yet

  Not checked in the free run.

• cites [67] Grissom NM,, Male-specific deficits in natural reward learning in a mouse model of neurodevelopmental disorders. Mol Psychiatry, 2017 23: p. 544– 555. 29038598 PMC5822461 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Taok2-deficient mice display reduced dendritic growth and deficient excitatory synaptic transmission in PFC through a mechanism involving reduced RhoA expression, suggesting that the 16p11.2 genes Kctd13 and Taok2 may act upon convergent downstream molecules.

“Taok2-deficient mice display reduced dendritic growth and deficient excitatory synaptic transmission in PFC through a mechanism involving the reduced RhoA expression [90], suggesting that the 16p11.2 genes Kctd13 and Taok2 may act upon convergent downstream molecules.”

• cites [90] Richter M,, Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling. Mol Psychiatry, 2019 24(9): p. 1329– 1350. 29467497 PMC6756231 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

These findings do not generalize to mice: two follow-up studies reported normal brain size in Kctd13-deficient mice.

“However, these findings do not generalize to mice: two follow-up studies reported normal brain size in Kctd13-deficient mice [82, 83].”

• cites [82] Escamilla CO,, Kctd13 deletion reduces synaptic transmission via increased RhoA. Nature, 2017 551(7679): p. 227– 231. 29088697 PMC5787033 sourceNot checked yet

  Not checked in the free run.

• cites [83] Arbogast T,, Kctd13-deficient mice display short-term memory impairment and sex-dependent genetic interactions. Hum Mol Genet, 2019 28(9): p. 1474– 1486. 30590535 PMC6489413 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Kctd13-deficient mice display reduced dendritic length/complexity and spine density, which is linked to downstream RhoA overexpression.

“Kctd13-deficient mice display reduced dendritic length/complexity and spine density, which is linked to downstream RhoA overexpression [82].”

• cites [82] Escamilla CO,, Kctd13 deletion reduces synaptic transmission via increased RhoA. Nature, 2017 551(7679): p. 227– 231. 29088697 PMC5787033 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In mice, Cul3 deficiency in the forebrain or PFC induces social interaction impairment and sensory-gating deficiency, as well as NMDA receptor hypofunction, whereas Cul3 loss in the striatum causes stereotypic behaviors, as well as cell type-specific changes in neuronal excitability.

“In mice, Cul3 deficiency in the forebrain or PFC induces social interaction impairment and sensory-gating deficiency, as well as NMDA receptor hypofunction, whereas Cul3 loss in the striatum causes stereotypic behaviors, as well as cell type-specific changes in neuronal excitability [87].”

• cites [87] Rapanelli M,, Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3. Mol Psychiatry, 2019(Epub ahead of print). 31455858 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

16p11.2dp/+ mice (Mills) display GABAergic synaptic deficits in mPFC pyramidal neurons and increased action potential firing rates.

“The 16p11.2dp/+ mice (Mills) display GABAergic synaptic deficits in mPFC pyramidal neurons and increased action potential firing rates [72].”

• cites [72] Rein B,, Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4. Mol Psychiatry, 2020(Epub ahead of print). PMC7483162 32099100 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Various structural abnormalities are reported in the striatum and cortex of 16p11.2+/− mice (Dolmetsch), along with an increased population of Drd2+ MSNs in the striatum and reduced Drd1+ neurons in the cortex.

“Various structural abnormalities are reported in the striatum and cortex of 16p11.2+/− mice (Dolmetsch), along with an increased population of Drd2+ MSNs in the striatum, and reduced Drd1+ neurons in the cortex [4].”

• cites [4] Portmann T,, Behavioral abnormalities and circuit defects in the basal ganglia of a mouse model of 16p11.2 deletion syndrome. Cell Reports, 2014 7: p. 1077– 1092. 24794428 PMC4251471 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Knockout of the 16p11.2 gene Taok2 produces cognitive and social deficits in mice, and also results in increased brain volume.

“Knockout of the 16p11.2 gene Taok2 produces cognitive and social deficits in mice, and also results in increased brain volume [90].”

• cites [90] Richter M,, Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling. Mol Psychiatry, 2019 24(9): p. 1329– 1350. 29467497 PMC6756231 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

RNA-sequencing identifies 2,344 and 1,504 significant differentially expressed genes in the cortex of 16p11.2+/− and 16p11.2dp/+ mice (Mills), respectively, as well as 908 and 1,290 nominally significant DEGs in lymphoblastoid cell lines from human 16p11.2 deletion or duplication carriers, respectively.

“RNA-sequencing identifies 2,344 and 1,504 significant differentially expressed genes (DEGs) in the cortex of 16p11.2+/− and 16p11.2dp/+ mice (Mills), respectively, as well as 908 and 1,290 nominally significant DEGs in lymphoblastoid cell lines (LCLs) from human 16p11.2 deletion or duplication carriers, respectively [76].”

• cites [76] Blumenthal I,, Transcriptional consequences of 16p11.2 deletion and duplication in mouse cortex and multiplex autism families. Am J Hum Genet, 2014 94(6): p. 870– 83. 24906019 PMC4121471 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Kctd13-deficient mice also display cognitive deficits in several memory tasks, raising the possibility that similar mechanisms may contribute to ID pathogenesis in 16p11.2 CNVs.

“Kctd13-deficient mice also display cognitive deficits in several memory tasks [83], raising the possibility that similar mechanisms may contribute to ID pathogenesis in 16p11.2 CNVs.”

• cites [83] Arbogast T,, Kctd13-deficient mice display short-term memory impairment and sex-dependent genetic interactions. Hum Mol Genet, 2019 28(9): p. 1474– 1486. 30590535 PMC6489413 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Recordings from CA1 of 16p11.2+/− mice (Herault) reveal intact synaptic transmission, along with modest but not statistically significant reductions in LTP.

“Recordings from CA1 of 16p11.2+/− mice (Herault) reveal intact synaptic transmission, along with modest but not statistically significant reductions in LTP [59].”

• cites [59] Arbogast T,, Reciprocal Effects on Neurocognitive and Metabolic Phenotypes in Mouse Models of 16p11.2 Deletion and Duplication Syndromes. PLoS Genet, 2016 12(2): p. e1005709. 26872257 PMC4752317 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Mouse models carrying 16p11.2 deletions or duplications reproduce many core behavioral phenotypes, such as social and cognitive deficits, and show altered synaptic function in multiple brain regions.

“Mice with 16p11.2 deletions or duplications recapitulate many core behavioral phenotypes, including social and cognitive deficits, and exhibit altered synaptic function across various brain areas.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The human 16p11.2 locus is a roughly 500-600 kb region containing 27-29 genes on the proximal short arm of chromosome 16.

“The human 16p11.2 gene locus (chromosome 16, position 11.2) is a ~500–600 kb region containing 27–29 genes [4–7] located on the proximal short arm of chromosome 16 [8].”

• cites [4] Portmann T,, Behavioral abnormalities and circuit defects in the basal ganglia of a mouse model of 16p11.2 deletion syndrome. Cell Reports, 2014 7: p. 1077– 1092. 24794428 PMC4251471 sourceNot checked yet

  Not checked in the free run.

• cites [5] Horev G,, Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism. PNAS, 2011 108(41): p. 17076– 17081. 21969575 PMC3193230 sourceNot checked yet

  Not checked in the free run.

• cites [6] Golzio C,, KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. Nature, 2012 485(7398): p. 363– 7. 22596160 PMC3366115 sourceNot checked yet

  Not checked in the free run.

• cites [7] Kumar VJ,, Linking spatial gene expression patterns to sex-specific brain structural changes on a mouse model of 16p11.2 hemideletion. Transl Psychiatry, 2018 8(1): p. 109. 29844452 PMC5974415 sourceNot checked yet

  Not checked in the free run.

• cites [8] Barber JC,, 16p11.2-p12.2 duplication syndrome; a genomic condition differentiated from euchromatic variation of 16p11.2. Eur J Hum Genet, 2013 21(2): p. 182– 9. 22828807 PMC3548261 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

16p11.2 deletions are associated with macrocephaly and obesity, while duplications often lead to microcephaly and low body weight/BMI.

“Deletions of 16p11.2 are associated with increased head circumference (macrocephaly) [10, 12, 17, 23] and obesity [10, 12, 16, 20], whereas duplications often result in below average head size (microcephaly) [10, 17, 23, 24] and low body weight/BMI [10, 24].”

• cites [10] D'Angelo D,, Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities. JAMA Psychiatry, 2016 73(1): p. 20– 30. 26629640 PMC5894477 sourceNot checked yet

  Not checked in the free run.

• cites [12] Zufferey F,, A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. Journal of Medical Genetics, 2012 49: p. 660– 668. 23054248 PMC3494011 sourceNot checked yet

  Not checked in the free run.

• cites [17] Shinawi M,, Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. Journal of Medical Genetics, 2010 47(5): p. 332– 341. 19914906 PMC3158566 sourceNot checked yet

  Not checked in the free run.

• cites [23] Qureshi AY,, Opposing brain differences in 16p11.2 deletion and duplication carriers. J Neurosci, 2014 34(34): p. 11199– 211. 25143601 PMC4138332 sourceNot checked yet

  Not checked in the free run.

• cites [16] Rosenfeld JA,, Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications. Journal of Neurodevelopmental Disorders, 2010 2: p. 26– 38. 21731881 PMC3125720 sourceNot checked yet

  Not checked in the free run.

• cites [20] Walters RG,, A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature, 2010 463(7281): p. 671– 5. 20130649 PMC2880448 sourceNot checked yet

  Not checked in the free run.

• cites [24] Jacquemont S,, Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature, 2011 478(7367): p. 97– 102. 21881559 PMC3637175 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Deletions and duplications of 16p11.2 have highly pleiotropic phenotypic effects, with strong links to ASD, ID, motor/developmental delay, dysmorphic features, and epilepsy/seizures.

“Deletions and duplications of 16p11.2 have highly pleiotropic phenotypic effects, with strong links to ASD [8–19], ID [8, 10, 12, 14–16, 19–21], motor/developmental delay [8–10, 12, 13, 15–19, 22], dysmorphic features [8, 12, 16, 17, 22], and epilepsy/seizures [10, 12, 17].”

• cites [8] Barber JC,, 16p11.2-p12.2 duplication syndrome; a genomic condition differentiated from euchromatic variation of 16p11.2. Eur J Hum Genet, 2013 21(2): p. 182– 9. 22828807 PMC3548261 sourceNot checked yet

  Not checked in the free run.

• cites [9] McCarthy SE,, Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet, 2009 41(11): p. 1223– 7. 19855392 PMC2951180 sourceNot checked yet

  Not checked in the free run.

• cites [10] D'Angelo D,, Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities. JAMA Psychiatry, 2016 73(1): p. 20– 30. 26629640 PMC5894477 sourceNot checked yet

  Not checked in the free run.

• cites [11] Kumar RA,, Recurrent 16p11.2 microdeletions in autism. Human Molecular Genetics, 2008 17(4): p. 628– 638. 18156158 sourceNot checked yet

  Not checked in the free run.

• cites [12] Zufferey F,, A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. Journal of Medical Genetics, 2012 49: p. 660– 668. 23054248 PMC3494011 sourceNot checked yet

  Not checked in the free run.

• cites [13] Weiss LA,, Association between microdeletion and microduplication at 16p11.2 and autism. The New England Journal of Medicine, 2008 358: p. 667– 675. 18184952 sourceNot checked yet

  Not checked in the free run.

• cites [14] Maillard AM,, The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity. Molecular Psychiatry, 2014 20: p. 140– 147. 25421402 PMC4320286 sourceNot checked yet

  Not checked in the free run.

• cites [15] Hanson E,, Cognitive and behavioral characterization of 16p11.2 deletion syndrome. Journal of Developmental & Behavioral Pediatrics, 2010 31: p. 649– 657. 20613623 sourceNot checked yet

  Not checked in the free run.

• cites [16] Rosenfeld JA,, Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications. Journal of Neurodevelopmental Disorders, 2010 2: p. 26– 38. 21731881 PMC3125720 sourceNot checked yet

  Not checked in the free run.

• cites [17] Shinawi M,, Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. Journal of Medical Genetics, 2010 47(5): p. 332– 341. 19914906 PMC3158566 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The penetrance of any pediatric phenotype in 16p11.2 deletion carriers is estimated at 62.4%, compared with 11.2% in duplication carriers.

“One study estimates that the penetrance of any pediatric phenotype in deletion carriers is 62.4%, relative to only 11.2% in duplication carriers [37].”

• cites [37] Rosenfeld JA,, Estimates of penetrance for recurrent pathogenic copy-number variations. Genet Med, 2013 15(6): p. 478– 81. 23258348 PMC3664238 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

De novo and inherited 16p11.2 duplication carriers show no differences in most clinical outcomes and on cognitive tests.

“De novo and inherited duplication carriers also show no differences in most clinical outcomes [19], and on cognitive tests [10].”

• cites [19] Green Snyder L,, Autism Spectrum Disorder, Developmental and Psychiatric Features in 16p11.2 Duplication. J Autism Dev Disord, 2016 46(8): p. 2734– 48. 27207092 sourceNot checked yet

  Not checked in the free run.

• cites [10] D'Angelo D,, Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities. JAMA Psychiatry, 2016 73(1): p. 20– 30. 26629640 PMC5894477 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

A predictive algorithm estimated 16p11.2 deletions at 1 in 3,021 live births and duplications at 1 in 4,216.

“A predictive algorithm estimated 16p11.2 deletions to affect 1 in every 3,021 live births, and duplications 1 in every 4,216 [30].”

• cites [30] Gillentine MA,, An estimation of the prevalence of genomic disorders using chromosomal microarray data. J Hum Genet, 2018 63(7): p. 795– 801. 29691480 PMC6019170 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Several studies of ID penetrance in 16p11.2 CNV carriers used clinically ascertained populations, so the ID penetrance estimate may be exaggerated.

“Note that several of these studies were conducted in clinically ascertained populations of 16p11.2 CNV carriers, so the estimate of ID penetrance may be exaggerated.”

May combine two claims.

The more severe outcomes associated with 16p11.2 deletions prevent these patients from having children, leading to lower rates of inherited deletions.

“The more severe outcomes associated with 16p11.2 deletions preclude these patients from having children, resulting in lower rates of inherited deletions [34].”

• cites [34] Niarchou M,, Psychiatric disorders in children with 16p11.2 deletion and duplication. Transl Psychiatry, 2019 9(1): p. 8. 30664628 PMC6341088 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Genetics Home Reference estimates that 16p11.2 deletions and duplications each affect about 3 in every 10,000 individuals.

“Genetics Home Reference estimates that 16p11.2 deletions and duplications each affect about 3 in every 10,000 individuals [28, 29].”

• cites [28] Genetics Home Reference 16p11.2 deletion Available from: https://ghr.nlm.nih.gov/condition/16p112-deletion-syndrome#statistics.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [29] Genetics Home Reference 16p11.2 duplication Available from: https://ghr.nlm.nih.gov/condition/16p112-duplication#statistics.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Genetic screenings of ASD patients repeatedly identify 16p11.2 deletions and duplications, placing them among the strongest genetic risk factors for ASD.

“Genetic screenings of ASD patients repeatedly identify 16p11.2 deletions & duplications, placing them among the strongest genetic risk factors for ASD [11, 13, 16, 38].”

• cites [11] Kumar RA,, Recurrent 16p11.2 microdeletions in autism. Human Molecular Genetics, 2008 17(4): p. 628– 638. 18156158 sourceNot checked yet

  Not checked in the free run.

• cites [13] Weiss LA,, Association between microdeletion and microduplication at 16p11.2 and autism. The New England Journal of Medicine, 2008 358: p. 667– 675. 18184952 sourceNot checked yet

  Not checked in the free run.

• cites [16] Rosenfeld JA,, Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications. Journal of Neurodevelopmental Disorders, 2010 2: p. 26– 38. 21731881 PMC3125720 sourceNot checked yet

  Not checked in the free run.

• cites [38] Marshall CR,, Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet, 2008 82(2): p. 477– 88. 18252227 PMC2426913 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

16p11.2 duplications are similarly associated with speech articulation abnormalities, speech delay, and language deficits.

“Duplications are similarly associated with speech articulation abnormalities [36], speech delay [17, 19], and language deficits [16].”

• cites [36] Steinman KJ,, 16p11.2 deletion and duplication: Characterizing neurologic phenotypes in a large clinically ascertained cohort. Am J Med Genet A, 2016 170(11): p. 2943– 2955. 27410714 sourceNot checked yet

  Not checked in the free run.

• cites [17] Shinawi M,, Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. Journal of Medical Genetics, 2010 47(5): p. 332– 341. 19914906 PMC3158566 sourceNot checked yet

  Not checked in the free run.

• cites [19] Green Snyder L,, Autism Spectrum Disorder, Developmental and Psychiatric Features in 16p11.2 Duplication. J Autism Dev Disord, 2016 46(8): p. 2734– 48. 27207092 sourceNot checked yet

  Not checked in the free run.

• cites [16] Rosenfeld JA,, Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications. Journal of Neurodevelopmental Disorders, 2010 2: p. 26– 38. 21731881 PMC3125720 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Speech articulation abnormalities, phonological processing disorder, language or communication disorder, speech or language deficits, and speech delay are present at high rates in 16p11.2 deletion carriers.

“Speech articulation abnormalities [36], phonological processing disorder [21, 23], language or communication disorder [14, 21, 23], speech or language deficits [15, 16], and speech delay [17, 33] are present at high rates in deletion carriers.”

• cites [36] Steinman KJ,, 16p11.2 deletion and duplication: Characterizing neurologic phenotypes in a large clinically ascertained cohort. Am J Med Genet A, 2016 170(11): p. 2943– 2955. 27410714 sourceNot checked yet

  Not checked in the free run.

• cites [21] Hanson E,, The cognitive and behavioral phenotype of the 16p11.2 deletion in a clinically ascertained population. Biological Psychiatry, 2015 77: p. 785– 793. 25064419 PMC5410712 sourceNot checked yet

  Not checked in the free run.

• cites [23] Qureshi AY,, Opposing brain differences in 16p11.2 deletion and duplication carriers. J Neurosci, 2014 34(34): p. 11199– 211. 25143601 PMC4138332 sourceNot checked yet

  Not checked in the free run.

• cites [14] Maillard AM,, The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity. Molecular Psychiatry, 2014 20: p. 140– 147. 25421402 PMC4320286 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

16p11.2 duplications predispose robustly to SZ and associated psychotic symptoms, with greater penetrance than 16p11.2 deletions.

“Thus, 16p11.2 duplications predispose robustly to SZ and associated psychotic symptoms, with greater penetrance than 16p11.2 deletions.”

May combine two claims.

MRI studies show reciprocal brain volume changes, with increased gray/white matter in 16p11.2 deletions and decreased gray/white matter in 16p11.2 duplications.

“MRI studies show reciprocal brain volume changes, with increased gray/white matter in 16p11.2 deletions, and decreased gray/white matter in 16p11.2 duplications [14, 23, 49, 50].”

• cites [14] Maillard AM,, The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity. Molecular Psychiatry, 2014 20: p. 140– 147. 25421402 PMC4320286 sourceNot checked yet

  Not checked in the free run.

• cites [23] Qureshi AY,, Opposing brain differences in 16p11.2 deletion and duplication carriers. J Neurosci, 2014 34(34): p. 11199– 211. 25143601 PMC4138332 sourceNot checked yet

  Not checked in the free run.

• cites [49] Martin-Brevet S,, Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study. Biol Psychiatry, 2018 84(4): p. 253– 264. 29778275 sourceNot checked yet

  Not checked in the free run.

• cites [50] Cardenas-de-la-Parra A,, Developmental trajectories of neuroanatomical alterations associated with the 16p11.2 Copy Number Variations. Neuroimage, 2019 203: p. 116155. 31494251 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

16p11.2 deletions are present at higher-than-expected rates in obese individuals and are more prevalent in developmental delay patients with obesity than those without obesity.

“16p11.2 deletions are present at higher-than-expected rates in obese individuals [31], and are more prevalent in developmental delay (DD) patients with obesity than those without obesity [20].”

• cites [31] Crawford K,, Medical consequences of pathogenic CNVs in adults: analysis of the UK Biobank. J Med Genet, 2019 56(3): p. 131– 138. 30343275 sourceNot checked yet

  Not checked in the free run.

• cites [20] Walters RG,, A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature, 2010 463(7281): p. 671– 5. 20130649 PMC2880448 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

16p11.2 duplications have reduced cortical thickness, reduced hippocampal volume, and enlarged ventricles.

“16p11.2 duplications also have the reduced cortical thickness [14, 23], reduced hippocampal volume [49] and enlarged ventricles [50, 53, 55].”

• cites [14] Maillard AM,, The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity. Molecular Psychiatry, 2014 20: p. 140– 147. 25421402 PMC4320286 sourceNot checked yet

  Not checked in the free run.

• cites [23] Qureshi AY,, Opposing brain differences in 16p11.2 deletion and duplication carriers. J Neurosci, 2014 34(34): p. 11199– 211. 25143601 PMC4138332 sourceNot checked yet

  Not checked in the free run.

• cites [49] Martin-Brevet S,, Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study. Biol Psychiatry, 2018 84(4): p. 253– 264. 29778275 sourceNot checked yet

  Not checked in the free run.

• cites [50] Cardenas-de-la-Parra A,, Developmental trajectories of neuroanatomical alterations associated with the 16p11.2 Copy Number Variations. Neuroimage, 2019 203: p. 116155. 31494251 sourceNot checked yet

  Not checked in the free run.

• cites [53] Owen JP,, Brain MR Imaging Findings and Associated Outcomes in Carriers of the Reciprocal Copy Number Variation at 16p11.2. Radiology, 2018 286(1): p. 217– 226. 28786752 sourceNot checked yet

  Not checked in the free run.

• cites [55] Filges I,, Brain MRI abnormalities and spectrum of neurological and clinical findings in three patients with proximal 16p11.2 microduplication. Am J Med Genet A, 2014 164A(8): p. 2003– 12. 24891046 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

16p11.2 deletions and duplications are linked to depression and anxiety.

“16p11.2 deletions and duplications are linked to several other psychiatric conditions, including depression [14, 47] and anxiety [12, 14, 18, 19, 23, 34].”

• cites [14] Maillard AM,, The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity. Molecular Psychiatry, 2014 20: p. 140– 147. 25421402 PMC4320286 sourceNot checked yet

  Not checked in the free run.

• cites [47] Kendall KM,, Association of Rare Copy Number Variants With Risk of Depression. JAMA Psychiatry, 2019 76(8): p. 818– 825. PMC6583866 30994872 sourceNot checked yet

  Not checked in the free run.

• cites [12] Zufferey F,, A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. Journal of Medical Genetics, 2012 49: p. 660– 668. 23054248 PMC3494011 sourceNot checked yet

  Not checked in the free run.

• cites [18] Fernandez BA,, Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16p11.2 in individuals ascertained for diagnosis of autism spectrum disorder. J Med Genet, 2010 47(3): p. 195– 203. 19755429 sourceNot checked yet

  Not checked in the free run.

• cites [19] Green Snyder L,, Autism Spectrum Disorder, Developmental and Psychiatric Features in 16p11.2 Duplication. J Autism Dev Disord, 2016 46(8): p. 2734– 48. 27207092 sourceNot checked yet

  Not checked in the free run.

• cites [23] Qureshi AY,, Opposing brain differences in 16p11.2 deletion and duplication carriers. J Neurosci, 2014 34(34): p. 11199– 211. 25143601 PMC4138332 sourceNot checked yet

  Not checked in the free run.

• cites [34] Niarchou M,, Psychiatric disorders in children with 16p11.2 deletion and duplication. Transl Psychiatry, 2019 9(1): p. 8. 30664628 PMC6341088 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Sleep abnormalities and anxiety have been reported in 16p11.2+/− mice (Mills).

“Sleep abnormalities [69, 70] and anxiety [66] have been reported in 16p11.2+/− mice (Mills).”

• cites [69] Lu HC,, Altered sleep architecture, rapid eye movement sleep, and neural oscillation in a mouse model of human chromosome 16p11.2 microdeletion. Sleep, 2019 42(3). PMC7850008 30541142 sourceNot checked yet

  Not checked in the free run.

• cites [70] Angelakos CC,, Hyperactivity and male-specific sleep deficits in the 16p11.2 deletion mouse model of autism. Autism Research, 2017 10: p. 572– 584. 27739237 PMC6201314 sourceNot checked yet

  Not checked in the free run.

• cites [66] Pucilowska J,, The 16p11.2 deletion mouse model of autism exhibits altered cortical progenitor proliferation and brain cytoarchitecture linked to the ERK MAPK pathway. J Neurosci, 2015 35(7): p. 3190– 200. 25698753 PMC6605601 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

16p11.2+/− mice display impairments in cognition, sociability and motor function, coinciding with phenotypes present in human 16p11.2 deletion carriers.

“16p11.2+/− mice display impairments in cognition, sociability and motor function, coinciding with phenotypes present in human 16p11.2 deletion carriers.”

May combine two claims.

These mice are deaf, which likely underlies startle/PPI deficits and may be related to altered ultrasonic vocalizations.

“However, these mice are deaf [60], which likely underlies startle/PPI deficits and may be related to altered ultrasonic vocalizations.”

• cites [60] Yang M,, 16p11.2 deletion syndrome mice display sensory and ultrasonic vocalization deficits during social interactions. Autism Research, 2015 8(5): p. 507– 521. 25663600 PMC5321681 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

16p11.2+/− mice may represent a suitable preclinical model system for evaluating mechanisms of certain social and cognitive dysfunctions, but several deficits associated with 16p11.2 deletions cannot be modeled in these animals.

“Thus, 16p11.2+/− mice may represent a suitable preclinical model system for evaluating mechanisms of certain social and cognitive dysfunctions, but several of the deficits associated with 16p11.2 deletions cannot be modeled in these animals.”

May combine two claims.

16p11.2dp/+ mice recapitulate several, but not all, human 16p11.2 duplication phenotypes, including social deficits, repetitive behaviors, and cognitive impairment.

“These studies indicate that 16p11.2dp/+ mice recapitulate several, but not all, human 16p11.2 duplication phenotypes, including social deficits, repetitive behaviors, and cognitive impairment.”

May combine two claims.

Synaptic phenotypes in 16p11.2+/− mice vary across brain areas, suggesting that 16p11.2 deletion may cause region- or cell-type-specific impairments.

“Synaptic phenotypes in 16p11.2+/− mice evidently vary across brain areas, suggesting that 16p11.2 deletion may cause region- or cell-type-specific impairments.”

May combine two claims.

The reduced brain size in 16p11.2+/− mice is associated with reduced body weight phenotype, suggesting that at least in part, a broader developmental physiological impairment might be involved.

“The precise reasons for the reduced brain size remain unclear, although the reduced brain size is associated with reduced body weight phenotype in 16p11.2+/− mice, suggesting that at least in part, a broader developmental physiological impairment might be involved.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

Results from rodent studies of individual genes need to be considered with caution, as the phenotypes of 16p11.2 CNVs may depend on the collective effects of multiple genes in the 16p11.2 locus.

“Additionally, results from rodent studies of individual genes need to be considered with caution, as the phenotypes of 16p11.2 CNVs may depend on the collective effects of multiple genes in 16p11.2 locus.”

May combine two claims.

Chemogenetic activation of the prefrontal cortex increases NMDAR phosphorylation and function and improves social and cognitive deficits in 16p11.2 hemideletion mice.

“Chemogenetic activation of PFC leads to increased NMDAR phosphorylation and function, resulting in amelioration of social and cognitive deficits [62].”

• cites [62] Wang W,, Chemogenetic Activation of Prefrontal Cortex Rescues Synaptic and Behavioral Deficits in a Mouse Model of 16p11.2 Deletion Syndrome. J Neurosci, 2018 38(26): p. 5939– 5948. 29853627 PMC6021990 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

16p11.2 duplication mice show no significant brain volume differences from wild-type mice, although several regions show trends toward smaller volume.

“No significant differences were found between 16p11.2dp/+ (Mills) and WT mice, though trends toward reduced volume were observed in several regions [5].”

• cites [5] Horev G,, Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism. PNAS, 2011 108(41): p. 17076– 17081. 21969575 PMC3193230 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

R-baclofen and several mGluR5 negative allosteric modulators have failed in clinical trials for Fragile X patients.

“However, R-baclofen and several mGluR5 NAMs have produced negative results in clinical trials with Fragile X patients [98].”

• cites [98] Berry-Kravis EM,, Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome. Nat Rev Drug Discov, 2018 17(4): p. 280– 299. 29217836 PMC6904225 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Restoring Npas4 expression reverses GABAergic deficits and improves social and cognitive deficits in 16p11.2 duplication mice, but does not affect repetitive grooming.

“a recent study from our group [72] revealed that restoring expression of Npas4, a key regulator of GABA synapses [104, 105] reverses GABAergic deficits and ameliorates social and cognitive deficits in these mice, but not repetitive grooming behavior.”

• cites [72] Rein B,, Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4. Mol Psychiatry, 2020(Epub ahead of print). PMC7483162 32099100 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

R-baclofen does not alter hyperlocomotion or ultrasonic vocalizations in 16p11.2 hemideletion mice.

“R-baclofen improves performance of 16p11.2+/− mice in several cognitive tasks, while hyperlocomotion and USVs are unaffected [64].”

• cites [64] Stoppel LJ,, R-Baclofen Reverses Cognitive Deficits and Improves Social Interactions in Two Lines of 16p11.2 Deletion Mice. Neuropsychopharmacology, 2018 43(3): p. 513– 524. 28984295 PMC5770771 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

16p11.2 hemideletion mice show NMDAR deficits and reduced activity in prefrontal cortex pyramidal neurons.

“As reviewed earlier, 16p11.2+/− mice exhibit NMDAR deficits and hypoactivity in PFC pyramidal neurons [62].”

• cites [62] Wang W,, Chemogenetic Activation of Prefrontal Cortex Rescues Synaptic and Behavioral Deficits in a Mouse Model of 16p11.2 Deletion Syndrome. J Neurosci, 2018 38(26): p. 5939– 5948. 29853627 PMC6021990 sourceNot checked yet

  Not checked in the free run.