Arthrogryposis and pterygia as lethal end manifestations of genetically defined congenital myopathies

Abstract

Arthrogryposis multiplex congenita affects approximately 1 in 3,000 individuals of different ethnic backgrounds and displays an equal incidence in males and females. The underlying mechanism for congenital contracture of the joints is decreased fetal movement during intrauterine development. This disorder is associated with over 400 medical conditions and 350 known genes that display considerable variability in phenotypic expression. In this report, four fetal or perinatal autopsy cases of arthrogryposis were studied by gross morphology, microscopic histopathologic examination, and whole genome sequencing of postmortem DNA. Two stillborn sibling fetuses with arthrogryposis, pterygia, and amyoplasia had compound heterozygous pathogenic variants in NEB. A neonate with a histopathologic diagnosis of nemaline myopathy had a heterozygous de novo pathogenic variant in ACTA1. Another stillborn infant with pterygia and arthrogryposis had a heterozygous de novo likely pathogenic variant in BICD2. These cases demonstrate the utility of whole genome sequencing as the principal diagnostic method of lethal forms of skeletal muscle disorders that present with arthrogryposis and muscle amyoplasia/hypoplasia. Molecular diagnosis provides an opportunity for studying patterns of inheritance and for family counseling concerning future pregnancies.

The Genotypic and Phenotypic Spectrum of BICD2 Variants in Spinal Muscular Atrophy

“…At the other end of the spectrum are severe cases with prenatal onset of severe hypotonia and joint contractures, and these patients often die in childhood. 16,19,20 Many of our patient's features were consistent with the severe form of SMALED2. However, until that time, only missense variants had been reported to cause disease.…”

“…We only became convinced that p.(N546del) was pathogenic after identifying a 12‐year‐old girl with similar features who also harbored the de novo deletion. While our manuscript was in preparation, Trimouille et al reported a family with SMALED caused by in‐frame deletion in BICD2 , p.(K508del), establishing that single amino acid deletions can also cause disease …”

“…At the mild end are cases such as that of a boy with late‐onset disease of mild course whose mother carried the same variant but was asymptomatic and a 70‐year‐old Brazilian man with a 40‐year history of slowly progressive gait difficulty in the setting of a presumably inherited variant. At the other end of the spectrum are severe cases with prenatal onset of severe hypotonia and joint contractures, and these patients often die in childhood …”

“…While our manuscript was in preparation, Trimouille et al 21 reported a family with SMALED caused by in-frame deletion in BICD2, p.(K508del), establishing that single amino acid deletions can also cause disease. 20 In January 2019, the curators of the Online Mendelian Inheritance in Man (OMIM) database revised the phenotype-gene relationships for BICD2 to reflect 2 distinct disorders. Classical SMALED2 was renamed SMA lower extremity-predominant type 2A (SMALED2A; MIM #615290).…”

Research platform for children with arthrogryposis multiplex congenita: Findings from the pilot registry

“…AMC has been previously described as being independent of sex (Darin, Kimber, Kroksmark, & Tulinius, ; Hall, ; Laitinen & Hirvensalo, ; Navti et al, ), and although X‐linked types of AMC exist, they are rare and there is no trend for a sex ratio (Ahmed et al, ). Although AMC seems to affect individuals from different ethnicities, AMC has been reported as more common in certain ethnic groups, for instance several types only reported in the Middle East (Bayram et al, ; Shohat et al, ).…”