A mild phenotype of LGI4-Related arthrogryposis multiplex congenita with intrafamilial variability
Shivani Mishra1, Archana Rai1, Priyanka Srivastava1
1Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, Uttar Pradesh, India.
Insights
Arthrogryposis multiplex congenita (AMC) is a rare genetic disorder. This study identifies a new LGI4 gene variant causing mild AMC, expanding knowledge of LGI4-related conditions.
Area of Science:
- Genetics
- Developmental Biology
- Clinical Medicine
Background:
- Arthrogryposis multiplex congenita (AMC) encompasses diverse congenital disorders marked by multiple joint contractures.
- LGI4-related AMC is a rare subtype, with limited documented cases and typically severe phenotypes.
Observation:
- A family presented with two children affected by AMC, one with a severe phenotype and early mortality.
- The second child exhibited a milder AMC phenotype with cognitive and speech delays, identified at 30 months.
Findings:
- Whole exome sequencing revealed a novel biallelic LGI4 gene variant in the affected child.
- Real-Time PCR confirmed a 50% reduction in LGI4 mRNA transcript levels, correlating with the milder phenotype.
- This discovery contributes to the LGI4 mutation spectrum and identifies the second reported case of mild AMC with an extended phenotype.
Implications:
- This study expands the understanding of LGI4 gene mutations in AMC, highlighting intrafamilial and interfamilial phenotypic variability.
- The findings suggest LGI4 variants can present with milder phenotypes and extended features, necessitating broader diagnostic considerations.
- Further research into LGI4 function may elucidate mechanisms underlying AMC and inform potential therapeutic strategies.
Abstract:
Arthrogryposis multiplex congenita (AMC) is a heterogeneous group of congenital disorders characterized by multiple joint contractures. We report a family with two children affected with AMC. First child had a severe AMC phenotype and died in infancy. Second child, currently 4-years-old, was ascertained at the age of 30 months with mild AMC phenotype with cognitive and speech delay. On whole exome sequencing, a novel biallelic sequence variant in initiation codon of LGI4 (leucine-rich glioma-inactivated 4) gene was identified in her. Real-Time PCR revealed 50% reduction in mRNA transcript levels in subject as compared to control which explains the milder phenotype. Till date, only four families with nine affected individuals with LGI4-related AMC have been reported. Except for one child surviving up to 6 years, all others were either terminated after prenatal diagnosis or succumbed in neonatal period. This study adds to mutation spectrum of LGI4 and reports the second case of mild AMC with extended phenotype. We review the existing phenotypic and genotypic information for the individuals with this condition and highlight the intrafamilial and interfamilial variability in these individuals.
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