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Just Expect It: Compound Heterozygous Variants of POMT1 in a Consanguineous Family—The Role of Next Generation Sequencing in Neuromuscular DisordersAcknowledgments The authors thank the family members who participated in this study. This work was supported by the Max Planck Society and by the European Commission Framework Program 7 (FP7) project GENCODYS with grant number 241995, the German Research Foundation (SFB665, SFB1315), the Berlin Institute of Health (BIH), the Charité, and the Förderverein für chronisch kranke Kinder am Sozialpädiatrischen Zentrum (SPZ) der Charité e.V.. The German Muscular Dystrophy Network (MD-NET 01GM0302) was funded by the German Ministry of Education and Research (BMBF, Bonn, Germany).
13 March 2019
24 July 2019
18 October 2019 (online)
Muscular dystrophy-dystroglycanopathies (MDDG) are a group of genetically heterogeneous autosomal recessive disorders characterized by hypoglycosylation of α-dystroglycan. Here, we report on two female patients from a consanguineous Lebanese family that presented in early infancy with generalized muscle hypotonia and primary microcephaly. Brain magnetic resonance imaging (MRI) showed different degrees of hypoplasia of the cerebellar vermis and hypoplasia of corpus callosum. Muscle biopsy analyses revealed a muscular dystrophy with reduced expression of α-dystroglycan and merosin in immunoblot analyses. Homozygosity mapping failed to elucidate the causal mutation due to the accepted notion that, in consanguineous families, homozygote mutations cause disease. However, by applying whole exome sequencing, we identified a novel compound heterozygous POMT1 mutation that segregates with the phenotype and is in line with the clinical presentation. This underscores that a less expected compound heterozygous instead of homozygous mutation in a consanguineous marriage results in a recessive disorder and highlights the growing role of next generation sequencing in neuromuscular disorder diagnostics.
Keywordscompound heterozygosity - consanguineous - POMT1 - congenital muscular dystrophy dystrogylcanopathies - developmental delay - microcephaly
* Equal contribution.
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