Expanding the MYBPC1 phenotypic spectrum: a novel homozygous mutation causes arthrogryposis multiplex congenita

Abstract

Arthrogryposis multiplex congenita (AMC) is characterized by heterogeneous non-progressive multiple joint contractures appearing at birth. We present a consanguineous Israeli-Druze family with several members presenting with AMC. A variable intra-familial phenotype and pected autosomal recessive inheritance prompted molecular diagnosis by whole-exome sequencing. Variant analysis focused on rare homozygous changes, revealed a missense variant in MYBPC1, NM_002465:c.556G>A (p.E286K), affecting the last nucleotide of exon 8. This novel variant was not observed in the common variant databases and co-segregated as expected within the extended family.

MYBPC1 encodes a slow skeletal muscle isoform, essential for muscle contraction. Heterozygous mutations in this gene are associated with distal arthrogryposis types 1b and 2, whereas a homozygous nonsense mutation is implicated in one family with lethal congenital contractural syndrome 4. We present a novel milder MYBPC1 homozygous phenotype.

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