Variable Phenotypic Manifestations of Novel Compound Heterozygous CRPPA Variants in Two Iranian Siblings With Limb-Girdle Muscular Dystrophy.
- 1Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran.
- 2Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
- 3Neuromuscular Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Abstract
Background
Dystroglycanopathies are a clinically and genetically heterogeneous group of muscular dystrophies caused by impaired glycosylation of α-dystroglycan, with variants in multiple genes, including CRPPA, which is associated with a broad spectrum ranging from congenital muscular dystrophy to limb-girdle muscular dystrophy.Method
The proband underwent whole exome sequencing, while Sanger sequencing was used for segregation analysis and oligonucleotide array-CGH was performed to confirm the copy number variant.Results
We report two siblings harboring an identical novel compound heterozygous CRPPA genotype, comprising a novel c.267G>C missense variant and a deletion encompassing exons 9-10. Despite sharing the same genotype, the siblings showed marked phenotypic variability. The female sibling developed childhood-onset disease with proximal weakness involving both the upper and lower limbs, whereas the male sibling presented with late-onset disease and weakness confined to the proximal lower limbs, accompanied by markedly discordant serum creatine kinase levels (1193 vs. 460 U/L).Conclusion
These findings expand the mutational and clinical spectrum of CRPPA-related dystroglycanopathy, highlight marked intrafamilial phenotypic variability, and emphasize the importance of integrated single-nucleotide and copy number variant analysis in the genetic diagnosis of neuromuscular disorders.
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BibTeX
@article{alagha2026variable,
title = {{Variable Phenotypic Manifestations of Novel Compound Heterozygous CRPPA Variants in Two Iranian Siblings With Limb-Girdle Muscular Dystrophy.}},
author = {Parnian Alagha and Fatemeh Ahangari and Ariana Kariminejad and Aida Ghasemi and Soheila Gholami and Neda Sadatian and Roxana Kariminejad and Kimia Kahrizi and Ali Asghar Okhovat and Hossein Najmabadi},
journal = {Molecular genetics \& genomic medicine},
year = {2026},
month = oct,
doi = {10.1002/mgg3.70312},
url = {https://europepmc.org/article/MED/42910546},
note = {CC BY},
}
RIS
TY - JOUR
TI - Variable Phenotypic Manifestations of Novel Compound Heterozygous CRPPA Variants in Two Iranian Siblings With Limb-Girdle Muscular Dystrophy.
AU - Parnian Alagha
AU - Fatemeh Ahangari
AU - Ariana Kariminejad
AU - Aida Ghasemi
AU - Soheila Gholami
AU - Neda Sadatian
AU - Roxana Kariminejad
AU - Kimia Kahrizi
AU - Ali Asghar Okhovat
AU - Hossein Najmabadi
PY - 2026
DA - 2026/10/01
JO - Molecular genetics & genomic medicine
DO - 10.1002/mgg3.70312
UR - https://europepmc.org/article/MED/42910546
AB - Background Dystroglycanopathies are a clinically and genetically heterogeneous group of muscular dystrophies caused by impaired glycosylation of α-dystroglycan, with variants in multiple genes, including CRPPA, which is associated with a broad spectrum ranging from congenital muscular dystrophy to limb-girdle muscular dystrophy.Method The proband underwent whole exome sequencing, while Sanger sequencing was used for segregation analysis and oligonucleotide array-CGH was performed to confirm the copy number variant.Results We report two siblings harboring an identical novel compound heterozygous CRPPA genotype, comprising a novel c.267G>C missense variant and a deletion encompassing exons 9-10. Despite sharing the same genotype, the siblings showed marked phenotypic variability. The female sibling developed childhood-onset disease with proximal weakness involving both the upper and lower limbs, whereas the male sibling presented with late-onset disease and weakness confined to the proximal lower limbs, accompanied by markedly discordant serum creatine kinase levels (1193 vs. 460 U/L).Conclusion These findings expand the mutational and clinical spectrum of CRPPA-related dystroglycanopathy, highlight marked intrafamilial phenotypic variability, and emphasize the importance of integrated single-nucleotide and copy number variant analysis in the genetic diagnosis of neuromuscular disorders.
SN - 2324-9269
ER -