#620369
Table of Contents
A number sign (#) is used with this entry because of evidence that severe fetal congenital myopathy-22B (CMYO22B) is caused by homozygous or compound heterozygous mutation in the SCN4A gene (603967) on chromosome 17q23.
Biallelic mutation in the SCN4A gene can also cause classic congenital myopathy-22A (CMYO22A; 620351).
Severe fetal congenital myopathy-22B (CMYO22B) is an autosomal recessive muscle disorder characterized by in utero onset of severe muscle weakness manifest as fetal akinesia. The pregnancies are often complicated by polyhydramnios, and affected individuals develop fetal hydrops with pulmonary hypoplasia, severe joint contractures, and generalized muscle hypoplasia. Those who are born have respiratory failure resulting in death. Dysmorphic facial features may be present. The features in these patients overlap with fetal akinesia deformation sequence (FADS; see 208150) and lethal congenital contractures syndrome (LCCS; see 253310) (Zaharieva et al., 2016).
For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).
Zaharieva et al. (2016) reported 6 patients from 2 unrelated families (families 5 and 6) with severe fetal CMYO22B. All patients showed fetal hypokinesia or akinesia resulting in death in utero or shortly after birth due to severe generalized hypotonia and respiratory failure. Limb contractures and/or foot deformities (talipes) were apparent in utero. Most pregnancies were complicated by polyhydramnios and the affected fetuses had hydrops and pulmonary hypoplasia. Postmortem examination showed marked muscle hypoplasia, ascites, limb contractures, fractures, small thorax, and foot deformities. Several had dysmorphic facial features, including frontal bossing, deep-set eyes, flat nose, ear anomalies, retro- or micrognathia, and small or tented mouth.
The transmission pattern of CMYO22B in the families reported by Zaharieva et al. (2016) was consistent with autosomal recessive inheritance.
In 6 patients from 2 unrelated families (families 5 and 6) with CMYO22B, Zaharieva et al. (2016) identified homozygous or compound heterozygous mutations in the SCN4A gene. Three sibs in family 5 carried a homozygous missense mutation (P382T; 603967.0036) that was demonstrated to result in a complete loss-of-function with no detectable sodium current when expressed in HEK293 cells. Three sibs in family 6 were compound heterozygous for a missense mutation (M203K; 603967.0037) that was demonstrated to have a hypomorphic effect on channel function, and a nonsense mutation (Y1593X; 603967.0038) that was predicted to result in a complete loss of channel function. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. None of the carrier parents was affected, indicating that loss of function in only 1 SCN4A allele is insufficient to cause a clinical phenotype.
Zaharieva, I. T., Thor, M. G., Oates, E. C., van Karnebeek, C., Hendson, G., Blom, E., Witting, N., Rasmussen, M., Gabbett, M. T., Ravenscroft, G., Sframeli, M., Suetterlin, K., and 28 others. Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or 'classical' congenital myopathy. Brain 139: 674-691, 2016. [PubMed: 26700687, images, related citations] [Full Text]
DO: 0081355;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q23.3 | Congenital myopathy 22B, severe fetal | 620369 | Autosomal recessive | 3 | SCN4A | 603967 |
A number sign (#) is used with this entry because of evidence that severe fetal congenital myopathy-22B (CMYO22B) is caused by homozygous or compound heterozygous mutation in the SCN4A gene (603967) on chromosome 17q23.
Biallelic mutation in the SCN4A gene can also cause classic congenital myopathy-22A (CMYO22A; 620351).
Severe fetal congenital myopathy-22B (CMYO22B) is an autosomal recessive muscle disorder characterized by in utero onset of severe muscle weakness manifest as fetal akinesia. The pregnancies are often complicated by polyhydramnios, and affected individuals develop fetal hydrops with pulmonary hypoplasia, severe joint contractures, and generalized muscle hypoplasia. Those who are born have respiratory failure resulting in death. Dysmorphic facial features may be present. The features in these patients overlap with fetal akinesia deformation sequence (FADS; see 208150) and lethal congenital contractures syndrome (LCCS; see 253310) (Zaharieva et al., 2016).
For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).
Zaharieva et al. (2016) reported 6 patients from 2 unrelated families (families 5 and 6) with severe fetal CMYO22B. All patients showed fetal hypokinesia or akinesia resulting in death in utero or shortly after birth due to severe generalized hypotonia and respiratory failure. Limb contractures and/or foot deformities (talipes) were apparent in utero. Most pregnancies were complicated by polyhydramnios and the affected fetuses had hydrops and pulmonary hypoplasia. Postmortem examination showed marked muscle hypoplasia, ascites, limb contractures, fractures, small thorax, and foot deformities. Several had dysmorphic facial features, including frontal bossing, deep-set eyes, flat nose, ear anomalies, retro- or micrognathia, and small or tented mouth.
The transmission pattern of CMYO22B in the families reported by Zaharieva et al. (2016) was consistent with autosomal recessive inheritance.
In 6 patients from 2 unrelated families (families 5 and 6) with CMYO22B, Zaharieva et al. (2016) identified homozygous or compound heterozygous mutations in the SCN4A gene. Three sibs in family 5 carried a homozygous missense mutation (P382T; 603967.0036) that was demonstrated to result in a complete loss-of-function with no detectable sodium current when expressed in HEK293 cells. Three sibs in family 6 were compound heterozygous for a missense mutation (M203K; 603967.0037) that was demonstrated to have a hypomorphic effect on channel function, and a nonsense mutation (Y1593X; 603967.0038) that was predicted to result in a complete loss of channel function. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. None of the carrier parents was affected, indicating that loss of function in only 1 SCN4A allele is insufficient to cause a clinical phenotype.
Zaharieva, I. T., Thor, M. G., Oates, E. C., van Karnebeek, C., Hendson, G., Blom, E., Witting, N., Rasmussen, M., Gabbett, M. T., Ravenscroft, G., Sframeli, M., Suetterlin, K., and 28 others. Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or 'classical' congenital myopathy. Brain 139: 674-691, 2016. [PubMed: 26700687] [Full Text: https://doi.org/10.1093/brain/awv352]
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