Biallelic c.1263dupC in DOK7 results in fetal akinesia deformation sequence

Abstract

Fetal akinesia deformation sequence (FADS) is a clinically and genetically heterogeneous condition. Pathogenic variants in DOK7 are known to cause myasthenic syndrome, congenital, 10 (MIM#254300) and, rarely (reported in a single family) lethal FADS. Herein, we describe a biallelic variant c.1263dupC in DOK7, known to cause congenital myasthenic syndrome 10, causing lethal FADS in a consanguineous family. The present report illustrates wide phenotypic variability caused by biallelic pathogenic variants in DOK7. We also describe the second family with FADS due to pathogenic variants in DOK7.

Variants in DOK7 results in fetal akinesia deformation sequence: A case report and review of literature

“…3 However, this observation was refuted by Radhakrishnan et al, who reported the second case of FADS with biallelic variant, c.1263dupC reported earlier in homozygous state in patients with CMS, suggestive of phenotypic variability. 5 This report further strengthens the association of DOK7 with FADS and lack of genotype-phenotype correlation.…”

Clinical and molecular characteristics of 26 fetuses with lethal multiple congenital contractures

“…The variants in DOK7 (c.54+25_55‐38del, p.Tyr19Valfs*23) and RAPSN (c.133G>A, p.(Val45Met) and c.493G>A, p.(Val165Met)), each previously identified in trans with different pathogenic variants, have been shown in living patients with congenital myasthenic syndromes, but not in FADS phenotypes 14,22–27 . Of note, only two families with FADS have been previously identified with DOK7 variants to the best of our knowledge, and the homozygous deletion we report here further broadens the narrow molecular spectrum of DOK7‐associated FADS 28,29 . The ACTC1 variant (c.1121G>A, p.(Arg374His)), recently associated with a new form of distal arthrogryposis, is presented here as a novel genetic contributor to LMPS 15 .…”

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

“…FADS and LMPS are spectrum disorders [ 147 ]. Pathogenic variants of CHRNA1 [ 148 ], CHRND [ 148 ], RAPSN [ 39 , 40 , 147 , 148 ], DOK7 [ 147 , 149 ], and SLC18A3 [ 150 ] also cause LMPS/FADS. The phenotypes are again likely to be caused by embryonic immobility due to defective NMJ signal transmission.…”

“…Although the mechanisms are unknown, a DOK7 -CMS patient was responsive to steroid for 40 to 50 years [ 329 ]. In addition, 4 patients with FADS due to pathogenic variants of DOK7 were reported [ 147 , 149 ].…”