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Am J Hum Genet. 2014 Nov 6;95(5):611-21. doi: 10.1016/j.ajhg.2014.10.007. Epub 2014 Nov 6.

Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome.

Author information

1
Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK.
2
Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK; Centre for Translational Omics-GOSgene, UCL Institute of Child Health, London WC1N 1EH, UK.
3
Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK; Centre for Translational Omics-GOSgene, UCL Institute of Child Health, London WC1N 1EH, UK; Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
4
Histopathology Department, Great Ormond Street Hospital, London WC1N 3JH, UK.
5
NE Thames Regional Genetics Laboratory Service, London WC1N 3BH, UK.
6
UCL Institute of Neurology, London WC1N 3BG, UK; Department of Clinical Genetics, Guy's Hospital, London SE1 9RT, UK.
7
Developmental Biology and Cancer, UCL Institute of Child Health, London WC1N 1EH, UK.
8
Serviço de Genética Médica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, 3000-602 Coimbra, Portugal; University Clinic of Pediatrics, Faculty of Medicine, University of Coimbra, 3000-602 Coimbra, Portugal.
9
Serviço de Genética Médica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, 3000-602 Coimbra, Portugal.
10
Clinical Genetics, Great Ormond Street Hospital, London WC1N 3JH, UK.
11
Radiology, Great Ormond Street Hospital, London WC1N 3JH, UK.
12
Department of Genome Analysis, Academic Medical Center, University of Amsterdam, 1105AZ Amsterdam, the Netherlands.
13
UCL Institute of Neurology, London WC1N 3BG, UK.
14
Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK; Clinical Genetics, Great Ormond Street Hospital, London WC1N 3JH, UK.
15
Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK; Serviço de Genética Médica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, 3000-602 Coimbra, Portugal. Electronic address: sbsousa@chc.min-saude.pt.
16
Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK. Electronic address: p.stanier@ucl.ac.uk.

Erratum in

  • Am J Hum Genet. 2015 Jun 4;96(6):1008-9.

Abstract

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.

PMID:
25439728
PMCID:
PMC4225633
DOI:
10.1016/j.ajhg.2014.10.007
[Indexed for MEDLINE]
Free PMC Article

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