Identification of the CFTR c.1666A>G Mutation in Hereditary Inclusion Body Myopathy Using Next-Generation Sequencing Analysis.

Yan Lu,Mi Pang,Yu-Wei Da,Xin-Gang Li,Lin Lei,Min Wang,Yong-Biao Zhang,Li Di

doi:10.3389/fnins.2018.00329

Abstract

Hereditary Inclusion Body Myopathy (HIBM) is a rare autosomal dominant or recessive adult onset muscle disease which affects one to three individuals per million worldwide. This disease is autosomal dominant or recessive and occurs in adulthood. Our previous study reported a new subtype of HIBM linked to the susceptibility locus at 7q22.1-31.1. The present study is aimed to identify the candidate gene responsible for the phenotype in HIBM pedigree. After multipoint linkage analysis, we performed targeted capture sequencing on 16 members and whole-exome sequencing (WES) on 5 members. Bioinformatics filtering was performed to prioritize the candidate pathogenic gene variants, which were further genotyped by Sanger sequencing. Our results showed that the highest peak of LOD score (4.70) was on chromosome 7q22.1-31.1.We identified 2 and 22 candidates using targeted capture sequencing and WES respectively, only one of which as CFTRc.1666A>G mutation was well cosegregated with the HIBM phenotype. Using transcriptome analysis, we did not detect the differences of CFTR's mRNA expression in the proband compared with healthy members. Due to low incidence of HIBM and there is no other pedigree to assess, mutation was detected in three patients with duchenne muscular dystrophyn (DMD) and five patients with limb-girdle muscular dystrophy (LGMD). And we found that the frequency of mutation detected in DMD and LGMD patients was higher than that of being expected in normal population. We suggested that the CFTRc.1666A>G may be a candidate marker which has strong genetic linkage with the causative gene in the HIBM family.

Highlights

Hereditary inclusion body myopathy (HIBM) refers to a rare heterogeneous group of neuromuscular diseases with autosomal recessive or dominant inheritance, which is characterized by muscle fibers containing rimmed vacuoles and inclusions consisting of tubulofilaments with a diameter of 15–21 nm (Askanas and Engel, 1993, 1998; Broccolini and Mirabella, 2015)
Limited by the computational memory needed by MERLIN, some offspring were removed from analyzing
We again found that the highest peak of LOD score was on chromosome 7q22.1-31.1, which was defined as a core region that ranged from rs1617640 to rs2966478 (Figure 2A)

Summary

Introduction

Hereditary inclusion body myopathy (HIBM) refers to a rare heterogeneous group of neuromuscular diseases with autosomal recessive or dominant inheritance, which is characterized by muscle fibers containing rimmed vacuoles and inclusions consisting of tubulofilaments with a diameter of 15–21 nm (Askanas and Engel, 1993, 1998; Broccolini and Mirabella, 2015). The most common form of HIBM, known as GNE myopathy, is autosomal recessive (Nonaka et al, 1981; Nishino et al, 2002), and the other identified forms of HIBM are autosomal dominant. This disorder of GNE myopathy is mainly due to the UDP-Nacetylglucosamine 2-epimerase/Nacetylmannosamine kinase (GNE) gene mutations, leading to abnormal sialylation of glycoproteins and relentless muscle degeneration (Argov and Yarom, 1984; Eisenberg et al, 2001). Early diagnosis would understand disease progress and help avoid unnecessary therapeutic options for these patients (Das et al, 2016)

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Conclusion