Genetic epilepsy syndromesGene: SNX27
(From the ID panel)
Evidence from 2 publications suggests that DD, ID and seizures are part of the phenotype of individuals with biallelic SNX27 pathogenic variants :
Damseh, Danson et al (2015 - PMID: 25894286) first reported on a consanguineous family with 4 affected sibs, homozygous for an SNX27 pathogenic variant. Features incl. hypotonia soon after birth, failure to thrive, severely delayed psychomotor development with no milestone acquisition, occurrence of myoclonic seizures with 3 individuals deceased early. Exome sequencing in one revealed a few candidate variants, with an SNX27 frameshift one [NM_030918.6:c.515_516del - p.(His172Argfs*6) / absent from ExAC] being the only retained following Sanger segregation studies. Using fibroblasts from an affected individual, Western blot with an antibody which would also bind prior to the truncation site, was consistent with dramatically reduced/absent SNX27 truncated mutant protein. Protein levels of VPS35, a component of the retromer responsible for direct cargo binding (not mediated by a cargo adaptor as SNX27), were normal.
Parente et al (2019 - PMID: 31721175) reported on a 13-year-old male with motor and language delay, ADHD, ID (kindergarten academic level at the age of 13) and seizures with onset at the age of 9 years (GTC, with abnormal EEG and postical SV tachycardia). Variable physical findings were reported. White matter hyperintesities were noted upon initial brain MRI (but were less marked in subsequent ones). Initial genetic testing (Alexander's disease, CMA, FMR1) was normal. Exome revealed compound heterozygosity for 2 SNX27 variants (NM_030918.5/NM_001330723.1 both apply c.510C>G - p.Tyr170* and c.1295G>A - p.Cys432Tyr) each inherited from healthy carrier parents. There were no other potentially causative variants. A parental history of - isolated - late onset seizures was reported (so this individual may not be considered for the seizure phenotype here).
The authors also reported on a further 31-year old affected male. This individual had infantile hypotonia, poor eye contact with subsequent significant DD, seizures (febrile/afebrile T-C with onset at the age of 14m) and ID estimated in the severe range. Variable - though somewhat different - physical findings were reported. Initial work-up included basic metabolic testing, standard karyotype, FISH for 15q11 and subtelomeric regions and PHF6 genetic testing - all normal. Exome (and subsequent Sanger confirmation/parental studies) revealed compound heterozygosity for a missense and a frameshift variant (c.989G>A / p.Arg330His and c.782dupT / p.Leu262Profs*6 same in NM_001330723.1, NM_030918.6).
SNX27 encodes sorting nexin 27, a cargo adaptor for the retromer. The latter is a multi-protein complex essential for regulating the retrieval and recycling of transmembrane cargos from endosomes to the trans-Golgi network or the plasma membrane [Lucas et al 2016 - PMID: 27889239 / McNally et al 2018 - PMID: 30072228].
As summarized by Parente et al, the encoded protein by regulating composition of the cell surface influences several processes eg. neuronal excitability, synaptic plasticity, Wnt signaling etc. It has been shown to interact with surface receptors and their ligands including GIRK channels, 5-HT4, ionotropic glutamate receptors (incl. NMDA- and AMPA-type receptors) and mGluR5 [several refs. provided].
Knockout of Snx27 in mice resulted in embryonic lethality (16% hmz of the 25% expected), severe postnatal growth retardation and death within the first 3 weeks. Snx27(+/-) mice have normal neuroanatomy but exhibit cognitive deficits (in learning and memory) and defects in synaptic function/plasticity with reduced amounts of NMDA and AMPA receptors (Cai et al - PMID: 21300787, Wang et al - PMID: 23524343).
There is no associated phenotype in OMIM/G2P.
Created: 9 Dec 2019, 5:27 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures
gene: SNX27 was added gene: SNX27 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: SNX27 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SNX27 were set to 25894286; 31721175; 21300787; 23524343 Phenotypes for gene: SNX27 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures Penetrance for gene: SNX27 were set to Complete Review for gene: SNX27 was set to AMBER