Mutations in SNX14 Cause a Distinctive Autosomal-Recessive Cerebellar Ataxia and Intellectual Disability Syndrome

Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families. A homozygous splice site mutation was identified by Sanger sequencing of SNX14 in a third family, selected purely by phenotypic similarity. This discovery confirms that these characteristic features represent a distinct and recognizable syndrome. SNX14 encodes a cellular protein containing Phox (PX) and regulator of G protein signaling (RGS) domains. Weighted gene coexpression network analysis predicts that SNX14 is highly coexpressed with genes involved in cellular protein metabolism and vesicle-mediated transport. All three mutations either directly affected the PX domain or diminished SNX14 levels, implicating a loss of normal cellular function. This manifested as increased cytoplasmic vacuolation as observed in cultured fibroblasts. Our findings indicate an essential role for SNX14 in neural development and function, particularly in development and maturation of the cerebellum. Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families. A homozygous splice site mutation was identified by Sanger sequencing of SNX14 in a third family, selected purely by phenotypic similarity. This discovery confirms that these characteristic features represent a distinct and recognizable syndrome. SNX14 encodes a cellular protein containing Phox (PX) and regulator of G protein signaling (RGS) domains. Weighted gene coexpression network analysis predicts that SNX14 is highly coexpressed with genes involved in cellular protein metabolism and vesicle-mediated transport. All three mutations either directly affected the PX domain or diminished SNX14 levels, implicating a loss of normal cellular function. This manifested as increased cytoplasmic vacuolation as observed in cultured fibroblasts. Our findings indicate an essential role for SNX14 in neural development and function, particularly in development and maturation of the cerebellum. Intellectual disability (ID) syndromes with a small cerebellum constitute a clinically and genetically heterogeneous group of neurological disorders for which the underlying molecular etiology is diverse and established in only a small subset. Several different cellular mechanisms have been implicated including mutations in SIL1, coding for an endoplasmic reticulum resident cochaperone, which cause Marinesco-Sjogren syndrome (MSS [MIM 248800]);1Ezgu F. 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A. 2014; PubMed Scopus Google Scholar genetic analysis at the causal for of the and to by the at and was for the of of the clinical and facial in The family was by of homozygosity by whole-exome sequencing to identify in the implicated mapping was on the two and two affected and and and the This a of which and analysis of the the homozygous of on sequencing of the from family 1 was and on an by in a of with of at We the to the and for we A. M. E. A. K. A. K. D. S. M. M.A. The a for sequencing 2010; 20: PubMed Scopus Google Scholar and and and discovery and M.A. E. R. C. G. M.A. M. et for discovery and sequencing Genet. 2011; PubMed Scopus Google Scholar and analysis was the of from the of in to or homozygous we the number of from an to a causal This was a homozygous nonsense within at which is within the (Figures and Sanger sequencing on an that the mutation was homozygous in both affected sisters and as an autosomal in both and or in The SNX14 two of either the acid a or and a protein of as share the the PX Phox of G protein domain and domain The mutation was identified within an that for both on the and was to in a protein that either the including of the domain of SNX14 Mutations in of the three families in for families 1 and mutations in family the the deletion in and the of the within two in the of the SNX14 in for of of the SNX14 and the SNX14 protein the and of the mutations in the three families. The protein of two at the by the PX and domain the The deletion in family is to the and PX the splice site mutation in family of the PX in the in SNX14 at the the used for described by et and et The Portuguese individuals to for or not the described by et the the used for described by et and et The Portuguese individuals to for or not the described by et for with from family was the only who to which was at of the and of and at and are as two or of the cerebellar not the the used for described by et C. S. H. A. M. A. T. in a J. PubMed Scopus Google Scholar and et F. C. M. A. S. for Neurol. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar The Portuguese individuals to for or not the described by et C. S. H. A. M. A. T. in a J. PubMed Scopus Google Scholar for from family was the only who to which was at in a of the three families in for families 1 and mutations in family the the deletion in and the of the within two in the of the SNX14 in for of of the SNX14 and the SNX14 protein the and of the mutations in the three families. 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S. an for network 2008; PubMed Scopus Google Scholar This approach is in of related genes that are not G. of the in the a Med. 2011; PubMed Scopus Google Scholar This was to that SNX14 is highly coexpressed within a J.A. S.L. L. A. A. J.J. K. et of the human 2014; PubMed Scopus Google Scholar which is for genes involved in cellular protein metabolism protein and vesicle-mediated the and to vesicle-mediated This to cellular in and cell a to the an with a of and with identified in the and a normal and with and of for assessment and small and we from cultured from affected from of the three families and found to have cytoplasmic vacuolation with of including with of as in (Figures a of from affected individuals not for in a which a in the as in many and Lee J.A. and PubMed Google Scholar cultured from individuals with cytoplasmic in both individuals with and F. Krejci P. Li S. de Sousa C. Graham Jr., J.M. Hansmann I. He W. Porpora K. Wand D. Wertelecki W. et al.Phenotype-genotype correlations in patients with Marinesco-Sjögren syndrome.Clin. Genet. 2014; 86: 74-84Crossref PubMed Scopus (22) Google Scholar and the SNX14 phenotype share the of cerebellar atrophy, and SNX14 in individuals not an especially in or kinase in the normal for the individuals who have SNX14 et B. T. N. K. K. P. E. role of in development and of PubMed Scopus Google Scholar that not have an and are small and have and in to and particularly in the which for in recently S. R. J. R.S. J.E. synaptic and is in the brain of 2014; PubMed Scopus (26) Google Scholar and synaptic function was The study of Huang et S. R. J. R.S. J.E. synaptic and is in the brain of 2014; PubMed Scopus (26) Google Scholar to that Our individuals the mutation on either the or in of a is a for a role of SNX14 in synaptic A. A. A. J. C. D. B. et mutations a of human autosomal recessive with clinical PubMed Scopus Google Scholar is to implicated in disorders associated with in disorders associated with and intellectual 2012; Scopus Google Scholar and the of SNX14 Other genes coding especially of the family, cause ID syndromes and have a role in synaptic W. van J. N. signaling at the implications for intellectual PubMed Scopus Google Scholar a phenotypic is with OPHN1 a in which mutations cause an X-linked of ID associated with cerebellar facial features, and N. Chabrol B. Lossi A.M. Cardoso C. Guerrini R. Dobyns W.B. Raybaud C. Villard L. Mutations in the oligophrenin-1 gene (OPHN1) cause X linked congenital cerebellar hypoplasia.J. Med. Genet. 2003; 40: 441-446Crossref PubMed Scopus (94) Google Scholar, W. van J. N. signaling at the implications for intellectual PubMed Scopus Google Scholar an essential role for SNX14 with the and of cellular in human cerebellar development and We to the families who to We to the of for the and for sequencing at The and of of and for for an affected is by the was by a is a of and group is by of and the for at for and of Child is by the We the of the and is by the at for and of Child This report is by the The in are of the and not of the the for or the of with and The for presented are as of Mendelian in Mutations in SNX14 a and Intellectual et of of Genetics PDF