Exome sequencing in a consanguineous family clinically diagnosed with early-onset Alzheimer’s disease identifies a homozygous CTSF mutation
Open accessAbstract
We have previously reported the whole genome genotyping analysis of 2 consanguineous siblings clinically diagnosed with early onset Alzheimer's disease (AD). In this analysis, we identified several large regions of homozygosity shared between both affected siblings, which we suggested could be candidate loci for a recessive genetic lesion underlying the early onset AD in these cases. We have now performed exome sequencing in one of these siblings and identified the potential cause of disease: the CTSF c.1243G>A:p.Gly415Arg mutation in homozygosity. Biallelic mutations in this gene have been shown to cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis with some cases resembling the impairment seen in AD.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Lysosomes play an important role in CNS cell fate and development, and this role continues into adulthood, where lysosomes help maintain a set of quiescent neural stem cells for adult neurogenesis.
“Thus, even before cells become neurons, lysosomes play an important role in CNS cell fate and development, and this role continues into adulthood, where lysosomes help maintain a set of quiescent neural stem cells for adult neurogenesis.20”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [20]
The Discussion describes lysosomal lipopigment accumulation in adult-onset Kufs disease, not a role for lysosomes in CNS cell fate or development. Searches for quiescent neural stem cells and adult neurogenesis found no passage addressing their maintenance. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Autosomal Recessive Causes Likely in Early-Onset Alzheimer Disease
Wingo, T. S. (2012) · Archives of Neurology · doi:10.1001/archneurol.2011.221 · Cited by 265 · see citing works
Flagged first, then by citations
Research works printed but not linked: 21
- Arsov T Smith KR Damiano J Franceschetti S Canafoglia L Bromhead CJ Andermann E Vears DF Cossette P Rajagopalan S McDougall A Sofia V Farrell M Aguglia U Zini A Meletti S Morbin M Mullen S Andermann F Mole SE Bahlo M Berkovic SF Kufs disease, the major adult form of neuronal ceroid lipofuscinosis, caused by mutations in CLN6 Am J Hum Genet 2011 88 5 566 573 21549341 PMC3146726
- Benitez BA Alvarado D Cai Y Mayo K Chakraverty S Norton J Morris JC Sands MS Goate A Cruchaga C Exome-Sequencing Confirms DNAJC5 Mutations as Cause of Adult Neuronal Ceroid-Lipofuscinosis PLoS One 2011 6 11 e26741 PONE-D-11-16499 [pii] 22073189 PMC3208569
- Berkovic SF Carpenter S Andermann F Andermann E Wolfe LS Kufs' disease: a critical reappraisal Brain 1988 111 Pt 1 27 62 3284607
- Clarimon J Djaldetti R Lleo A Guerreiro RJ Molinuevo JL Paisan-Ruiz C Gomez-Isla T Blesa R Singleton A Hardy J Whole genome analysis in a consanguineous family with early onset Alzheimer's disease Neurobiology of aging 2009 30 12 1986 1991 18387709 PMC8950082
- DePristo MA Banks E Poplin R Garimella KV Maguire JR Hartl C Philippakis AA del Angel G Rivas MA Hanna M McKenna A Fennell TJ Kernytsky AM Sivachenko AY Cibulskis K Gabriel SB Altshuler D Daly MJ A framework for variation discovery and genotyping using next-generation DNA sequencing data Nat Genet 2011 43 5 491 498 21478889 PMC3083463
- Di Fabio R Moro F Pestillo L Meschini MC Pezzini F Doccini S Casali C Pierelli F Simonati A Santorelli FM Pseudo-dominant inheritance of a novel CTSF mutation associated with type B Kufs disease Neurology 2014 83 19 1769 1770 25274848
- Di Fede G Catania M Morbin M Rossi G Suardi S Mazzoleni G Merlin M Giovagnoli AR Prioni S Erbetta A Falcone C Gobbi M Colombo L Bastone A Beeg M Manzoni C Francescucci B Spagnoli A Cantu L Del Favero E Levy E Salmona M Tagliavini F A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis Science 2009 323 5920 1473 1477 19286555 PMC2728497
- Dolzhanskaya N Gonzalez MA Sperziani F Stefl S Messing J Wen GY Alexov E Zuchner S Velinov M A novel p.Leu(381)Phe mutation in presenilin 1 is associated with very early onset and unusually fast progressing dementia as well as lysosomal inclusions typically seen in Kufs disease J Alzheimers Dis 2014 39 1 23 27 24121961 PMC4013718
- Finn RD Bateman A Clements J Coggill P Eberhardt RY Eddy SR Heger A Hetherington K Holm L Mistry J Sonnhammer EL Tate J Punta M Pfam: the protein families database Nucleic acids research 2014 42 Database issue D222 D230 24288371 PMC3965110
- Ghani M Reitz C Cheng R Vardarajan BN Jun G Sato C Naj A Rajbhandary R Wang LS Valladares O Lin CF Larson EB Graff-Radford NR Evans D De Jager PL Crane PK Buxbaum JD Murrell JR Raj T Ertekin-Taner N Logue M Baldwin CT Green RC Barnes LL Cantwell LB Fallin MD Go RC Griffith PA Obisesan TO Manly JJ Lunetta KL Kamboh MI Lopez OL Bennett DA Hendrie H Hall KS Goate AM Byrd GS Kukull WA Foroud TM Haines JL Farrer LA Pericak-Vance MA Lee JH Schellenberg GD St George-Hyslop P Mayeux R Rogaeva E Alzheimer's Disease Genetics, C Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals JAMA Neurol 2015 72 11 1313 1323 26366463 PMC4641052
- Ghani M Sato C Lee JH Reitz C Moreno D Mayeux R St George-Hyslop P Rogaeva E Evidence of recessive Alzheimer disease loci in a Caribbean Hispanic data set: genome-wide survey of runs of homozygosity JAMA Neurol 2013 70 10 1261 1267 23978990 PMC3991012
- Li H Durbin R Fast and accurate short read alignment with Burrows-Wheeler transform Bioinformatics 2009 25 14 1754 1760 19451168 PMC2705234
- McKenna A Hanna M Banks E Sivachenko A Cibulskis K Kernytsky A Garimella K Altshuler D Gabriel S Daly M DePristo MA The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data Genome research 2010 20 9 1297 1303 20644199 PMC2928508
- McKhann G Drachman D Folstein M Katzman R Price D Stadlan EM Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease Neurology 1984 34 7 939 944 6610841
- Nalls MA Guerreiro RJ Simon-Sanchez J Bras JT Traynor BJ Gibbs JR Launer L Hardy J Singleton AB Extended tracts of homozygosity identify novel candidate genes associated with late-onset Alzheimer's disease Neurogenetics 2009 10 3 183 190 19271249 PMC2908484
- Noskova L Stranecky V Hartmannova H Pristoupilova A Baresova V Ivanek R Hulkova H Jahnova H van der Zee J Staropoli JF Sims KB Tyynela J Van Broeckhoven C Nijssen PC Mole SE Elleder M Kmoch S Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis Am J Hum Genet 2011 89 2 241 252 21820099 PMC3155175
- Sherva R Baldwin CT Inzelberg R Vardarajan B Cupples LA Lunetta K Bowirrat A Naj A Pericak-Vance M Friedland RP Farrer LA Identification of novel candidate genes for Alzheimer's disease by autozygosity mapping using genome wide SNP data J Alzheimers Dis 2011 23 2 349 359 21098978 PMC3819807
- Sims R Dwyer S Harold D Gerrish A Hollingworth P Chapman J Jones N Abraham R Ivanov D Pahwa JS Moskvina V Dowzell K Thomas C Stretton A Lovestone S Powell J Proitsi P Lupton MK Brayne C Rubinsztein DC Gill M Lawlor B Lynch A Morgan K Brown KS Passmore PA Craig D McGuiness B Todd S Johnston JA Holmes C Mann D Smith AD Love S Kehoe PG Hardy J Mead S Fox N Rossor M Collinge J Livingston G Bass NJ Gurling H McQuillin A Jones L Holmans PA O'Donovan M Owen MJ Williams J No evidence that extended tracts of homozygosity are associated with Alzheimer's disease American journal of medical genetics Part B, Neuropsychiatric genetics: the official publication of the International Society of Psychiatric Genetics 2011 156B 7 764 771 21812096
- Smith KR Dahl HH Canafoglia L Andermann E Damiano J Morbin M Bruni AC Giaccone G Cossette P Saftig P Grotzinger J Schwake M Andermann F Staropoli JF Sims KB Mole SE Franceschetti S Alexander NA Cooper JD Chapman HA Carpenter S Berkovic SF Bahlo M Cathepsin F mutations cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis Hum Mol Genet 2013 22 7 1417 1423 23297359 PMC3596852
- Tomiyama T Nagata T Shimada H Teraoka R Fukushima A Kanemitsu H Takuma H Kuwano R Imagawa M Ataka S Wada Y Yoshioka E Nishizaki T Watanabe Y Mori H A new amyloid beta variant favoring oligomerization in Alzheimer's-type dementia Ann Neurol 2008 63 3 377 387 18300294
- Williams RE Mole SE New nomenclature and classification scheme for the neuronal ceroid lipofuscinoses Neurology 2012 79 2 183 191 22778232
Cited by
Sorted by citations
Genetics of Alzheimer’s disease: where we are, and where we are going
Bellenguez, C., Grenier-Boley, B., & Lambert, J.-C. (2020) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2019.11.024 · Cited by 215 · see citing works
Lane-Donovan, C., Paredes, M., & Kao, A. W. (2025) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2025.102854 · Cited by 3 · see citing works
- Authors
- Bras, J., Djaldetti, R., Alves, A. M., Mead, S., Darwent, L., Lleo, A., Molinuevo, J. L., Blesa, R., Singleton, A., Hardy, J., Clarimon, J., & Guerreiro, R.
- Affiliations
- Tel Aviv University (IL)
- UCL Queen Square Institute of Neurology (GB)
- MRC Prion Unit (GB)
- Universitat Autònoma de Barcelona (ES)
- National Institutes of Health (US)
- Corresponding author
- Guerreiro, Rita
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 46
- Pages
- 236.e1-236.e6
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC5166571
- OpenAlex
- W2469973380
- Cited by
- 27
- References
- 1
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 1 · 2022: 4 · 2021: 6 · 2020: 4 · 2019: 2 · 2018: 2 · 2017: 4
- FWCI
- 2.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Medical Research Council
- National Institute of Health Research's Biomedical Research Centre
- UCL Hospitals NHS Foundation Trust
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- early-onset Alzheimer's disease, cystatin F, homozygous mutation, consanguinity, homozygosity mapping, neuronal ceroid lipofuscinosis, exome sequencing
- MeSH terms
- Aged, Alzheimer Disease, Consanguinity, Homozygote, Humans, Male, Middle Aged, Mutation, Neuronal Ceroid-Lipofuscinoses, Sequence Analysis, Siblings, Genome-Wide Association Study, Cathepsin F, Exome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
