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A Common CHAT Gene Mutation of Congenital Myasthenic Syndrome Found in Kadazandusun Children
Khian Aun Tan1, Hui Bein Chew2, Yusnita Yacob3
1Pediatric Neurology Unit, Hospital Tunku Azizah, Kuala Lumpur, Malaysia.
Insights
Congenital myasthenic syndrome (CMS) is a rare inherited neuromuscular disorder. Genetic analysis identified a potential founder mutation in the CHAT gene within the Kadazandusun population, aiding diagnosis.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Congenital myasthenic syndrome (CMS) is a rare inherited neuromuscular junction disorder with diverse clinical presentations.
- Diagnostic challenges include difficulties with pediatric neurophysiology and lack of specific markers.
- Next-generation sequencing (NGS) has improved the identification of novel mutations.
Purpose of the Study:
- To describe the diagnostic journey and treatment of three Congenital Myasthenic Syndrome patients.
- To investigate genetic mutations in patients from Kadazandusun kinships.
- To explore the potential founder effect of a specific mutation in this ethnic group.
Main Methods:
- Clinical case study of three Congenital Myasthenic Syndrome patients.
- Genetic analysis using next-generation sequencing.
- Follow-up treatment and clinical observation.
Main Results:
- Two siblings with a consanguineous marriage presented with homozygous mutations (c.916G>C, p.Val306Leu) in the CHAT gene.
- A third patient had compound heterozygous mutations (c.406G>A, p.Val136Met and c.916G>C, p.Val306Leu) in the CHAT gene.
- The p.Val306Leu mutation is postulated as a founder mutation in the Kadazandusun population.
Conclusions:
- NGS technology facilitates the diagnosis of Congenital Myasthenic Syndrome.
- The identified CHAT gene mutations provide insight into the genetic basis of CMS in this population.
- The p.Val306Leu mutation may represent a significant founder mutation for CMS in the Kadazandusuns.
Abstract:
Congenital myasthenic syndrome (CMS) is an uncommon inherited neuromuscular junction disease. The clinical presentation of this disorder is diverse. Typically patients with this disorder present with early-onset swallowing difficulty and apnea in infancy, fluctuating ocular palsies and fatigable proximal muscle weakness during childhood, and late-onset form involving progressive weakness in adulthood. Difficulty in performing neurophysiology studies in children and the absence of a pathognomonic investigation marker increase the challenges in diagnosis of this disorder. The emergence of next-generation sequencing technology has circumvented these challenges somewhat, and has contributed to the discovery of novel mutations. We present here diagnostic odyssey of three CMS patients from two unrelated Kadazandusun kinships and their follow-up treatment. A rare homozygous mutation c.916G > C (p.Val306Leu) in CHAT gene was found in two siblings born of a consanguineous marriage. Third patient had compound heterozygous mutations c.406G > A (p.Val136Met) and c.916G > C (p.Val306Leu) in CHAT gene. We postulate that p.Val306Leu may be a founder mutation in the Kadazandusuns, an indigenous ethnic minority of Borneo Island.
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