Abstract
BackgroundHereditary sensory and autonomic neuropathy (HSAN) type II is a group of extremely rare autosomal recessive neurological disorders with heterogeneous clinical and genetic characteristics.MethodsWe performed high-depth next-generation targeted sequencing using a custom-ordered “HSAN” panel, covering WNK1, NTRK1, NGF, SPTLC1 and IKBKAP genes, to identify pathogenic variants of the proband as well as the family members. We also performed whole exome sequencing to further investigate the potential occurrence of additional pathogenic variants in genes that were not covered by the “HSAN” panel. Quantitative real-time PCR was used to identify pathogenic copy number variations (CNVs) and to analyze the mRNA level of WNK1 gene of the family. Western blot analysis was performed to evaluate the WNK1 protein expression level.ResultsAfter sequencing, a novel nonsense variant (c.2747 T > G, p.Leu916Ter) in exon 9 of WNK1 gene was identified in two patients (hemizygous) and their mother (heterozygous). This variant is absent in all public databases as well as in 600 Han Chinese healthy controls. The region of this variant is evolutionary highly conserved. Furthermore, by quantitative real-time PCR using DNA of the pedigree, we revealed a large deletion containing the whole WNK1 gene in two patients. The WNK1 expression levels of the patients were significantly reduced.ConclusionsOur study firstly revealed that the coexistence of a novel WNK1 nonsense variant and a CNV resulted in HSAN type IIA in a Han Chinese family.
Highlights
Hereditary sensory and autonomic neuropathy (HSAN) type II is a group of extremely rare autosomal recessive neurological disorders with heterogeneous clinical and genetic characteristics
T > G, p.Leu916Ter) in exon 9 of WNK1 gene was identified in three samples
No extra potential pathogenic variants were identified in other HSAN-related genes, analyzed by whole-exome sequencing
Summary
Hereditary sensory and autonomic neuropathy (HSAN) type II is a group of extremely rare autosomal recessive neurological disorders with heterogeneous clinical and genetic characteristics. Hereditary sensory and autonomic neuropathies (HSAN), a group of extremely rare neurological diseases which are represented clinically and genetically heterogeneous, resulting in severe sensory dysfunction accompanied by variable degrees of autonomic dysfunction [1,2,3,4]. Mutations in at least 20 genes are HSAN type IIA (OMIM: 201300) is known as a subtype of HSAN type II [1, 9]. The pathogenic variants in WNK1 gene are responsible for HSAN type IIA [9]. Only 11 pathogenic variants in WNK1 have been reported causing HSAN in the ClinVar database [11]. CNVs are known to cause 10 times more
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