Recessive GNE Mutations in Korean Nonaka Distal Myopathy Patients with or without Peripheral Neuropathy.

Autosomal recessive Nonaka distal myopathy is a rare autosomal recessive genetic disease characterized by progressive degeneration of the distal muscles, causing muscle weakness and decreased grip strength. It is primarily associated with mutations in the GNE gene, which encodes a key enzyme of sialic acid biosynthesis (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase). This study was performed to find GNE mutations in six independent distal myopathy patients with or without peripheral neuropathy using whole-exome sequencing (WES). In silico pathogenic prediction and simulation of 3D structural changes were performed for the mutant GNE proteins. As a result, we identified five pathogenic or likely pathogenic missense variants: c.86T>C (p.Met29Thr), c.527A>T (p.Asp176Val), c.782T>C (p.Met261Thr), c.1714G>C (p.Val572Leu), and c.1771G>A (p.Ala591Thr). Five affected individuals showed compound heterozygous mutations, while only one patient revealed a homozygous mutation. Two patients revealed unreported combinations of combined heterozygous mutations. We observed some specific clinical features, such as complex phenotypes of distal myopathy with distal hereditary peripheral neuropathy, an earlier onset of weakness in legs than that of hands, and clinical heterogeneity between two patients with the same set of compound heterozygous mutations. Our findings on these genetic causes expand the clinical spectrum associated with the GNE mutations and can help prepare therapeutic strategies.

Biallelic mutations in pakistani families with autosomal recessive prelingual nonsyndromic hearing loss.

BACKGROUND: Nonsyndromic autosomal recessive hearing loss (DFNB) is an etiologically heterogeneous disorder group showing a wide spectrum of onset ages and severity. DFNB genes are very diverse in their types and functions, making molecular diagnosis difficult. DFNB is particularly frequent in Pakistan, which may be partly due to consanguinity. OBJECTIVE: This study was performed to determine the genetic causes in Pakistani DFNB families with prelingual onset and to establish genotype-phenotype correlation. METHODS: Whole exome sequencing and subsequent genetic analysis were performed for 11 Pakistani DFNB families including eight consanguineous families. RESULTS: We identified eight pathogenic or likely pathogenic mutations in LOXHD1, GJB2, SLC26A4, MYO15A, and TMC1 from six families. The GJB2 mutations were identified in two families each with compound heterozygous mutations and a homozygous mutation. The compound heterozygous mutations in LOXHD1 ([p.D278Y] + [p.D1219E]) and GJB2 [p.M1?] + [p.G12Vfs*2]) were novel. The four missense or start-loss mutations were located at well conserved residues, and most in silico analysis predicted their pathogenicity. In addition to causative mutations, we found compound heterozygous mutations in PTPRQ as variants of uncertain significance. CONCLUSION: This study identified biallelic mutations as the underlying cause of early onset DFNB in six Pakistani families. This study will be helpful in providing an exact molecular diagnosis and treatment of prelingual onset deafness patients.

Peripheral Myelin Protein 22 Gene Mutations in Charcot-Marie-Tooth Disease Type 1E Patients.

Duplication and deletion of the peripheral myelin protein 22 (PMP22) gene cause Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), respectively, while point mutations or small insertions and deletions (indels) usually cause CMT type 1E (CMT1E) or HNPP. This study was performed to identify PMP22 mutations and to analyze the genotype−phenotype correlation in Korean CMT families. By the application of whole-exome sequencing (WES) and targeted gene panel sequencing (TS), we identified 14 pathogenic or likely pathogenic PMP22 mutations in 21 families out of 850 CMT families who were negative for 17p12 (PMP22) duplication. Most mutations were located in the well-conserved transmembrane domains. Of these, eight mutations were not reported in other populations. High frequencies of de novo mutations were observed, and the mutation sites of c.68C>G and c.215C>T were suggested as the mutational hotspots. Affected individuals showed an early onset-severe phenotype and late onset-mild phenotype, and more than 40% of the CMT1E patients showed hearing loss. Physical and electrophysiological symptoms of the CMT1E patients were more severely damaged than those of CMT1A while similar to CMT1B caused by MPZ mutations. Our results will be useful for the reference data of Korean CMT1E and the molecular diagnosis of CMT1 with or without hearing loss.