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2023 ACMG Annual Clinical Genetics Meeting Digital ...
Evidence of Complex Inheritance Patterns in Limb-G ...
Evidence of Complex Inheritance Patterns in Limb-Girdle and other Muscular Dystrophies: Synergistic Heterozygosity and Multigenic Inheritance
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This study explored the possibility of complex inheritance patterns in limb-girdle and other muscular dystrophies (MDs). It was found that digenic or multigenic inheritance, involving alterations in two or more genes, may contribute to the disease presentation. The study used a comprehensive next-generation sequencing (NGS)-based multi-gene panel to analyze cases with pathogenic variants in multiple genes.<br /><br />Out of 6,473 cases with clinical suspicion of MD, molecular diagnosis was established in 19.6% (1,266 cases) using NGS-based panel testing. This suggests that multiple genes play a role in patients with MDs. In these cases, pathogenic variants were identified in two or more genes, leading to digenic or multigenic inheritance. Unusual complex clinical presentations were observed as a result of this inheritance pattern.<br /><br />A custom Agilent SureSelect targeted sequence capture was used to enrich all 66 genes included in the panel, followed by NGS. Sequence variants were analyzed using a proprietary analysis and interpretation pipeline. Variants with a frequency greater than expected were considered benign. Copy number variants (CNVs) were also analyzed using Biodiscovery's NxClinical software.<br /><br />The study identified 26 cases with pathogenic variants in multiple genes, including combinations of dominant-dominant, dominant-recessive, recessive-recessive, and dominant or recessive X-linked inheritance. These cases involved genes such as LDB3, DMD, TTN, DYSF, ANO5, PABPN1, COL6A1, FLNC, RYR1, GAA, LMNA, LYST, SYNE1, CLCN1, COL6A2, and NEB. These findings indicate the complex nature of MD disease presentation and suggest the need for further genotype-phenotype correlation studies.<br /><br />In conclusion, this study highlights the possible involvement of multiple genes in the development of MDs. Further research is needed to fully understand the complex inheritance mechanisms in different MD subtypes.
Asset Subtitle
Presenting Author - Madhuri Hegde, PhD, FACMG; Co-Author - Babi Nallamilli, PhD, FACMG; Co-Author - Yinghong Pan, PhD; Co-Author - Jagannathan Lakshmanan, PhD; Co-Author - Vinish Ramachander, PhD; Co-Author - Ruby Liu, PhD, CGC;
Meta Tag
Genetic Testing
Musculoskeletal system
NextGen Sequencing
Co-Author
Babi Nallamilli, PhD, FACMG
Co-Author
Yinghong Pan, PhD
Co-Author
Jagannathan Lakshmanan, PhD
Co-Author
Vinish Ramachander, PhD
Co-Author
Ruby Liu, PhD, CGC
Presenting Author
Madhuri Hegde, PhD, FACMG
Keywords
complex inheritance patterns
limb-girdle muscular dystrophies
multigenic inheritance
digenic inheritance
next-generation sequencing
pathogenic variants
gene panel testing
clinical suspicion of MD
dominant-dominant inheritance
MD subtypes
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