A novel mutation in KIAA0196: identification of a gene involved in Ritscher–Schinzel/3C syndrome in a First Nations cohort

Mutations in subunits of the SNX17-Retriever-CCC-WASH recycling pathway are involved in human pathologies primarily affecting the nervous system.

“Importantly, a growing body of evidence indicates that mutations in subunits of the SNX17-Retriever-CCC-WASH recycling pathway are involved in human pathologies primarily affecting the nervous system.”

The KIAA0196 mutation results in a 60% reduction in strumpellin levels.

“This mutation results in a 60% reduction in strumpellin levels31”

A homozygous splice site mutation in KIAA0196 causes Ritscher-Schinzel/3C syndrome (RSS) in a Canadian cohort.

“A homozygous splice site mutation in KIAA0196, which encodes the WASH component strumpellin, causes Ritscher–Schinzel/3C syndrome (RSS) in a Canadian cohort31.”

RSS patients share many clinical features with patients with CCDC22 mutations.

“RSS patients share many clinical features with patients with CCDC22 mutations, described thus far1831.”

Evidence that endosomal LDLR recycling may also be relevant in humans was so far restricted to rare loss-of-function mutations in CCDC22 and WASHC5, which cause hypercholesterolaemia but also developmental defects and intellectual disability.

“Evidence that the endosomal LDLR recycling may also be relevant in humans was so far restricted to rare loss-of-function mutations in CCDC22 and WASHC5, which cause hypercholesterolaemia but also developmental defects and intellectual disability.13,35,36”

RSS (3C syndrome) has a triad of clinical features including craniofacial features, cerebellar anomalies and cardiac defects.

“also known as 3C syndrome due to its triad of clinical features including craniofacial features, cerebellar anomalies and cardiac defects.”

CCDC22 and WASHC5 are responsible genes for Ritscher-Schinzel syndrome (RSS).

“CCDC22 and WASHC5 are known as responsible genes for Ritscher-Schinzel syndrome (RSS, MIM220210 and MIM300963)”

WASHC4 is a causative gene for autosomal recessive intellectual disability (MIM615817).

“WASHC4 has been reported as a causative gene for autosomal recessive intellectual disability (MIM615817)”

To date, approximately 37 variants in WASHC5, including three splice mutations and one gross deletion variant, have been identified in a range of phenotypes.

“To date, approximately 37 variants in WASHC5, including three splice mutations and one gross deletion variant, have been identified in a range of phenotypes (Elliott et al., 2013; Mulroy et al., 2021; D'Amore et al., 2018; Ma et al., 2018).”

The WASHC5 mutation c.3335+2T>A results in skipping of exon 27 near the C-terminus.

“This mutation, c.3335+2T>A, results in skipping of exon 27 near the C-terminus”

A biallelic splice-site mutation at the C-terminus of WASHC5 has been reported in numerous members of a First Nations community in northern Manitoba, Canada who have Ritscher-Schinzel/3C syndrome (RSS), a disorder characterized by distinctive craniofacial features as well as cerebellar and cardiac abnormalities.

“A biallelic splice-site mutation at the C-terminus has been reported in numerous members of a First Nations community in northern Manitoba, Canada with Ritscher-Schinzel/3C syndrome (RSS), a disorder characterized by distinctive craniofacial features as well as cerebellar and cardiac abnormalities (50).”

One patient sample with the c.3335+2T>A WASHC5 mutation showed a 60% reduction in strumpellin protein.

“one patient sample showed a 60% reduction in strumpellin protein”