Abstract
Objective: The article aims to provide genetic counseling to a family with two children who were experiencing growth and developmental delays.
Methods: Clinical information of the proband was collected. Peripheral blood was collected from core family members to identify the initial reason for growth and developmental delays by whole exome sequencing (WES) and Sanger sequencing. To ascertain the consequences of the newly discovered variants, details of the variants detected were analyzed by bioinformatic tools. Furthermore, we performed in vitro experimentation targeting SNX14 gene expression to confirm whether the variants could alter the expression of SNX14.
Results: The proband had prenatal ultrasound findings that included flattened frontal bones, increased interocular distance, widened bilateral cerebral sulci, and shortened long bones, which resulted in subsequent postnatal developmental delays. The older sister also displayed growth developmental delays and poor muscle tone. WES identified compound heterozygous variants of c.712A>T (p.Arg238Ter) and .2744A>T (p.Gln915Leu) in the SNX14 gene in these two children. Both are novel missense variant that originates from the father and mother, respectively. Sanger sequencing confirmed this result. Following the guideline of the American College of Medical Genetics and Genomics (ACMG), the SNX14 c.712A>T (p.Arg238Ter) variant was predicted to be pathogenic (P), while the SNX14 c.2744A>T (p.Gln915Leu) variant was predicted to be a variant of uncertain significance (VUS). The structural analysis revealed that the c.2744A>T (p.Gln915Leu) variant may impact the stability of the SNX14 protein. In vitro experiments demonstrated that both variants reduced SNX14 expression.
Conclusion: The SNX14 gene c.712A>T (p.Arg238Ter) and c.2744A>T (p.Gln915Leu) were identified as the genetic causes of growth and developmental delay in two affected children. This conclusion was based on the clinical presentations of the children, structural analysis of the mutant protein, and in vitro experimental validation. This discovery expands the range of SNX14 gene variants and provides a foundation for genetic counseling and guidance for future pregnancies in the affected children’s families.
Zhang H, Hong Y, Yang W, Wang R, Yao T, Wang J, Liu K, Yuan H, Xu C, Zhou Y, Li G, Zhang L, Luo H, Zhang X, Du D, Sun H, Zheng Q, Zhang YW, Zhao Y, Zhou Y, Xu H, Wang X. SNX14 deficiency-induced defective axonal mitochondrial transport in Purkinje cells underlies cerebellar ataxia and can be reversed by valproate. Natl Sci Rev. 2021 Feb 10;8(7):nwab024. doi: 10.1093/nsr/nwab024. PMID: 34691693; PMCID: PMC8310771.
Abstract
Loss-of-function mutations in sorting nexin 14 (SNX14) cause autosomal recessive spinocerebellar ataxia 20, which is a form of early-onset cerebellar ataxia that lacks molecular mechanisms and mouse models. We generated Snx14-deficient mouse models and observed severe motor deficits and cell-autonomous Purkinje cell degeneration. SNX14 deficiency disrupted microtubule organization and mitochondrial transport in axons by destabilizing the microtubule-severing enzyme spastin, which is implicated in dominant hereditary spastic paraplegia with cerebellar ataxia, and compromised axonal integrity and mitochondrial function. Axonal transport disruption and mitochondrial dysfunction further led to degeneration of high-energy-demanding Purkinje cells, which resulted in the pathogenesis of cerebellar ataxia. The antiepileptic drug valproate ameliorated motor deficits and cerebellar degeneration in Snx14-deficient mice via the restoration of mitochondrial transport and function in Purkinje cells. Our study revealed an unprecedented role for SNX14-dependent axonal transport in cerebellar ataxia, demonstrated the convergence of SNX14 and spastin in mitochondrial dysfunction, and suggested valproate as a potential therapeutic agent.
Levchenko O, Filatova A, Mishina I, Antonenko A, Skoblov M. Homozygous deep intronic variant in SNX14 cause autosomal recessive Spinocerebellar ataxia 20: a case report. Front Genet. 2023 Jul 6;14:1197681. doi: 10.3389/fgene.2023.1197681. PMID: 37485342; PMCID: PMC10359490.
Abstract
Autosomal recessive spinocerebellar ataxia type 20, SCAR20 (MIM: 616354) is a rare syndromic form of hereditary ataxias. It characterized by the presence of progressive ataxia, intellectual developmental disorder, autism and dysmorphic features. The disease caused by biallelic variants in SNX14 gene that lead to loss of protein function. Typically, these variants result in the formation of a premature stop codon, a shift in the reading frame or a variant in canonical splicing sites, as well as gross rearrangements. Here we present the first case of a deep intronic variant c.462-589A>G in SNX14 identified in two sisters with SCAR20 from a consanguineous family. This variant resulted in the inclusion of a pseudo-exon 82 nucleotides long and the formation of a premature stop codon, leading to the production of a truncated protein (NP_722523.1:p.Asp155Valfs*8). Following an extensive diagnostic search, the diagnosis was confirmed using trio whole genome sequencing. This case contributes to expanding the spectrum of potential genetic variants associated with SCAR20.
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