Neurogenetic fetal akinesia and arthrogryposis: genetics, expanding genotype-phenotypes and functional genomics

Abstract

BackgroundFetal akinesia and arthrogryposis are clinically and genetically heterogeneous and have traditionally been refractive to genetic diagnosis. The widespread availability of affordable genome-wide sequencing has facilitated accurate genetic diagnosis and gene discovery in these conditions.MethodsWe performed next generation sequencing (NGS) in 190 probands with a diagnosis of arthrogryposis multiplex congenita, distal arthrogryposis, fetal akinesia deformation sequence or multiple pterygium syndrome. This sequencing was a combination of bespoke neurogenetic disease gene panels and whole exome sequencing. Only class 4 and 5 variants were reported, except for two cases where the identified variants of unknown significance (VUS) are most likely to be causative for the observed phenotype. Co-segregation studies and confirmation of variants identified by NGS were performed where possible. Functional genomics was performed as required.ResultsOf the 190 probands, 81 received an accurate genetic diagnosis. All except two of these cases harboured class 4 and/or 5 variants based on the American College of Medical Genetics and Genomics guidelines. We identified phenotypic expansions associated with CACNA1S, CHRNB1, GMPPB and STAC3. We describe a total of 50 novel variants, including a novel missense variant in the recently identified gene for arthrogryposis with brain malformations—SMPD4.ConclusionsComprehensive gene panels give a diagnosis for a substantial proportion (42%) of fetal akinesia and arthrogryposis cases, even in an unselected cohort. Recently identified genes account for a relatively large proportion, 32%, of the diagnoses. Diagnostic-research collaboration was critical to the diagnosis and variant interpretation in many cases, facilitated genotype-phenotype expansions and reclassified VUS through functional genomics.

Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita

“…35 More recently, Ravenscroft et al performed next generation sequencing in 190 probands and 81 of them received a genetic diagnosis (42.6%). 31 In our cohort of 315 AMC families, the largest one reported to date, our results indicate that WES is the most efficient approach with an ability of disease gene identification in 61% of AMC index patients. Our data showed indeed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of recently published novel genes.…”

“…Variants in STAC3 are responsible for Bailey-Bloch congenital myopathy (MIM: 255995 25 ) and were more recently reported in AMC. 31 Variants in USP9X are known to be responsible for female-restricted X linked syndromic mental retardation (MIM: 300968 26 ). Our data indicate a critical role of these genes in prenatal motor development leading to AMC broadening the phenotypic spectrum of variants in these genes.…”

Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy

“…Both dominant and recessive mutations caused a decrease in DHPR function in skeletal muscle, with a decrease in protein level and a relevant impairment of Ca 2+ release induced by the sarcolemma depolarization in cultured myotubes. A further case of congenital myopathy with ophthalmoplegia has been reported by Hunter and collaborators [ 57 ]; two additional severe cases with fetal akinesia leading to premature termination of pregnancy at 26 weeks of gestation or death after 10 days of were reported by Ravenscroft and collaborators [ 58 ]. Three Turkish siblings carrying homozygous CACNA1S mutation presented a congenital myopathy with additional features, including cognitive delay, pes equinovarus deformity, and neurogenic changes at muscle biopsy [ 59 ].…”

Models of Distal Arthrogryposis and Lethal Congenital Contracture Syndrome

“…About 1 in 3000 live births presents with some form of arthrogryposis, many of which are nonprogressive and improve with physiotherapy. The core root of arthrogryposis is fetal akinesia, or lack of fetal movement, that results in contractures forming in the joints [1][2][3]. Movement is required for normal joint development; it influences the structure of the joints, as well as promoting cellular signaling that guides normal tissue development.…”