Arthrogryposis as a Syndrome: Gene Ontology Analysis

Abstract

Arthrogryposis by definition has multiple congenital contractures. All types of arthrogryposis have decreased in utero fetal movement. Because so many things are involved in normal fetal movement, there are many causes and processes that can go awry. In this era of molecular genetics, we have tried to place the known mutated genes seen in genetic forms of arthrogryposis into biological processes or cellular functions as defined by gene ontology. We hope this leads to better identification of all interacting pathways and processes involved in the development of fetal movement in order to improve diagnosis of the genetic forms of arthrogryposis, to lead to the development of molecular therapies, and to help better define the natural history of various types of arthrogryposis.

Fetal arthrogryposis multiplex congenita/fetal akinesia deformation sequence (FADS)—Aetiology, diagnosis, and management

“…The diagnosis of these cases can be delineated based on a detailed neurological examination, developmental assessment, imaging, nerve conduction velocity, and electromyography. The numerous genetic defects underlying aetiologies of arthrogryposis are extensively reviewed by Hall and Keifer and Beecroft et al…”

“…Arthrogryposis is a feature of more than 400 distinct disorders, of which more than 50% have an underlying genetic diagnosis . The current genes reported to be associated with arthrogryposis are reviewed in Hall and Kiefer and Beecroft et al Ongoing studies using whole exome and genome sequencing will likely continue identifying genetic causes of AMC . To date, arthrogryposis has been associated with autosomal dominant, autosomal recessive (homozygous and compound heterozygous), and X‐linked modes of inheritance as well as mitochondrial, chromosome, and epigenetic abnormalities.…”

“…Prenatal diagnosis, however, is challenging, and fetal arthrogryposis or its underlying aetiology is frequently not identified prior to delivery. The literature reports that 26% to 66.7% of cases are detected prenatally, and the detection depends on the ultrasound operator and the machine resolution . Access to and advanced ultrasound technology including 3D ultrasound and diagnostic genetic tests have changed the landscape of prenatal diagnosis.…”

Survival among children with “Lethal” congenital contracture syndrome 11 caused by novel mutations in the gliomedin gene ( GLDN )

“…Severity of the AMC phenotype is heterogeneous ranging from limited limb involvement to more extensive neurologic deficits including central nervous system impairment. AMC has been associated with chromosomal abnormalities (Reed, Hall, Riccardi, Aylsworth, & Timmons, 1985), mitochondrial disorders (von Kleist-Retzow et al, 2003), and sporadic and inherited mutations in more than 220 genes, including genes that regulate central nervous system development (neuronal axonogenesis, Schwann and glial cell development), skeletal muscle, synaptic transmission, and glycoprotein metabolism (Bayram et al, 2016;Hall & Kiefer, 2016;Narkis, Landau, Manor, Ofir, & Birk, 2007). Recently, the first association of biallelic GLDN (MIM# 608603) mutations with a lethal form of AMC (LCCS11; MIM# 617194) was reported in four unrelated families (Maluenda et al, 2016).…”

The Clinic Is My Laboratory: Life as a Clinical Geneticist

“…We also wrote a book for families and therapists, which is now available online (139). We defined many specific clinical entities and their natural histories, and more recently have contributed to finding more than 330 genes that, when mutated, can lead to decreased fetal movement and subsequently multiple congenital contractures (83). Similar clinics and clinical research on rare diseases were being established at many centers in the 1970s, and individual clinical geneticists became experts on particular disorders (e.g., the contributions of Vic Ricardi and Jan Friedman to neurofibromatosis).…”