title: Identification of the rare compound heterozygous variants in the NEB gene in a Korean family with intellectual disability, epilepsy and early-childhood-onset generalized muscle weakness.
abstract: We examined a Korean family with complex phenotypes characterized by intellectual disability, epilepsy and early-childhood-onset generalized muscle weakness. Since we did not find any abnormality using several conventional genetic tests for detection of chromosomal aberrations, gene copy number variations and mitochondrial gene mutations, we aimed to identify disease-causing genetic alteration(s) in this family. We conducted whole-exome sequencing (WES) in this family. After filtering the WES data, we compared five exome sequences of two affected siblings, one unaffected sibling and the unaffected parents, and we determined the allele frequency of the identified variants in an Asian population. Finally, we selected one candidate variant pair which is unique in the patients and corresponds to an autosomal recessive genetic model. The two affected siblings had the same compound heterozygous variation in the NEB gene encoding nebulin, which was composed of two different missense variants: c.2603T>C (p.L868P) in exon 27 and c.21340C>T (p.R7114W) in exon 143. We confirmed these variations by Sanger sequencing. On the basis of the fundamental role of nebulin in the brain and skeletal muscles, we concluded that this compound heterozygous NEB variation may be a sound candidate for the disease-causing mutation in this family. Since the patients are characterized by generalized muscle weakness together with neurodevelopmental phenotypes, it is suggested that NEB mutations could manifest more diverse phenotypes than those previously described.
authors.affiliation: 1] Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea [2] Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea.
authors.forename: Hyun-Seok
authors.initials: HS
authors.lastname: Jin
authors.affiliation: Department of Physical Medicine and Rehabilitation, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Jong-Bin
authors.initials: JB
authors.lastname: Lee
authors.affiliation: 1] Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea [2] Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Kyung
authors.initials: K
authors.lastname: Kim
authors.affiliation: 1] Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea [2] Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Ki-Young
authors.initials: KY
authors.lastname: Lee
authors.affiliation: 1] Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea [2] Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea.
authors.forename: Vit-Na
authors.initials: VN
authors.lastname: Choi
authors.affiliation: Theragen BiO Institute, Suwon, Republic of Korea.
authors.forename: Jong-Soo
authors.initials: JS
authors.lastname: Kim
authors.affiliation: 1] Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea [2] Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea.
authors.forename: Seon-Yong
authors.initials: SY
authors.lastname: Jeong
authors.affiliation: 1] Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea [2] Department of Physical Medicine and Rehabilitation, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Shin-Young
authors.initials: SY
authors.lastname: Yim
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D002648:Child; D056915:DNA Copy Number Variations / Q000235:genetics; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D018908:Muscle Weakness / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D056910:Republic of Korea; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D009124:Muscle Proteins; C035620:nebulin