Deficiency of the myogenic factor MyoD causes a perinatally lethal fetal akinesia - PubMed
Deficiency of the myogenic factor MyoD causes a perinatally lethal fetal akinesia
Christopher M Watson et al. J Med Genet. 2016 Apr.
Abstract
Background: Lethal fetal akinesia deformation sequence (FADS) describes a clinically and genetically heterogeneous phenotype that includes fetal akinesia, intrauterine growth retardation, arthrogryposis and developmental anomalies. Affected babies die as a result of pulmonary hypoplasia. We aimed to identify the underlying genetic cause of this disorder in a family in which there were three affected individuals from two sibships.
Methods: Autosomal-recessive inheritance was suggested by a family history of consanguinity and by recurrence of the phenotype between the two sibships. We performed exome sequencing of the affected individuals and their unaffected mother, followed by autozygosity mapping and variant filtering to identify the causative gene.
Results: Five autozygous regions were identified, spanning 31.7 Mb of genomic sequence and including 211 genes. Using standard variant filtering criteria, we excluded all variants as being the likely pathogenic cause, apart from a single novel nonsense mutation, c.188C>A p.(Ser63*) (NM_002478.4), in MYOD1. This gene encodes an extensively studied transcription factor involved in muscle development, which has nonetheless not hitherto been associated with a hereditary human disease phenotype.
Conclusions: We provide the first description of a human phenotype that appears to result from MYOD1 mutation. The presentation with FADS is consistent with a large body of data demonstrating that in the mouse, MyoD is a major controller of precursor cell commitment to the myogenic differentiation programme.
Keywords: MYOD1; exome sequencing; fetal akinesia; lung hypoplasia; perinatal lethal.
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Figures

A pedigree showing the relationship between affected (shaded symbols) and unaffected (outlined symbols) individuals.

Affected infant III:2 showing (A) facial dysmorphism including a tall forehead with bitemporal narrowing, a long philtrum and a small chin; (B) the right hand showing long tapered fingers with contractures and (C) the left foot with overlapping toes. Affected infant III:4 showing (D) facial dysmorphism including a square forehead and small chin; apparent deficiency of pectoralis and proximal limb musculature (E and F) contractures of the proximal interphalangeal joints in the right and left hand, respectively.

Autozygous intervals shared between all three affected individuals (dark blue) are shown with respect to per-sample autozygous intervals identified in affected individuals (light blue) and the unaffected mother (pink). The concentric circles, beginning from the interior, represent samples II:2, III:2, III:1 and III:4.
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