A number sign (#) is used with this entry because of evidence that congenital myopathy-9A (CMYP9A) is caused by homozygous mutation in the FXR1 gene (600819) on chromosome 3q28. One such family has been reported.

Biallelic mutation in the FXR1 gene also causes congenital myopathy-9B (CMYP9B; 618823), which is less severe.

Congenital myopathy-9A (CMYP9A) is an autosomal recessive early-onset severe muscular disorder resulting in early death. Affected individuals present at birth with neonatal hypotonia, poor feeding, fractures of the long bones, and respiratory insufficiency. Laboratory investigations are consistent with a defect in early muscle development (summary by Estan et al., 2019).

For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).

Estan et al. (2019) reported 3 sibs, born of consanguineous Egyptian parents (family 1), with a lethal form of congenital myopathy. The proband was a male infant born from a pregnancy characterized by decreased fetal movements and oligohydramnios. At birth, he had severe hypotonia, multiple fractures of the long bones, weak cry, respiratory insufficiency, and episodes of unexplained tachycardia necessitating admission to the neonatal intensive care unit for a month. He had a short neck, skeletal deformities, joint hyperlaxity, ulnar deviation of the hands, laterally deviated feet, and hypoplastic genitalia with cryptorchidism. He died at 5 months of age. A previously born female sib, who was similarly affected, died at 70 days of age. A subsequent pregnancy showed lack of fetal movement, suggesting the same condition; that pregnancy was terminated. Muscle biopsy was not performed, although studies on patient-derived myoblasts and myotubes showed the presence of abnormal cytoplasmic granules.

The transmission pattern of CMYP9A in the family reported by Estan et al. (2019) was consistent with autosomal recessive inheritance.

In a male infant and his affected fetus sib, conceived of consanguineous Egyptian parents (family 1), with CMYP9A, Estan et al. (2019) identified a homozygous 4-bp deletion (c.1764_1767delACAG; 600819.0001) at the 3-prime end of exon 15 of the FXR1 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Primary myoblasts derived from 1 of the patients showed the presence of truncated 82- and 84-kD proteins, consistent with escape from nonsense-mediated mRNA decay (NMD). These abnormal proteins were localized in ring-shaped cytoplasmic granules that contained mRNA. Skeletal muscle from mutant mice carrying the homologous 4-bp deletion showed similar abnormalities (see ANIMAL MODEL).

Estan et al. (2019) found that inactivation of all isoforms of Fxr1 specifically in skeletal muscle myoblasts in mice resulted in neonatal lethality. Generation of the 4-bp deletion (ACAGdel) in exon 15 of the Fxr1 gene, similar to the mutation found in the family with MYORIBF, caused a myopathic phenotype in mice, with decreased body weight, muscle mass, muscle strength, and bone mineral density compared to controls. Skeletal muscle from mutant mice showed reduced fiber size, increased central nuclei, predominance of type 1 fibers, and cores devoid of NADH-TR enzymatic activity. Transmission electron microscopy showed disintegration of Z-bands and sarcomere structure, or disorganized Z-lines and Z-line streaming with abnormal mitochondrial accumulation. RT-PCR analysis showed that the ACAGdel mutation escaped nonsense mediated mRNA decay and resulted in Fxr1 expression at 74.7% of control levels. The mutant truncated protein resulting from the ACAGdel mutation was detected in cytoplasmic granules that contained mRNA, but were not stress granules, suggesting altered mRNA trafficking; this was confirmed by the finding of differentially expressed genes. These findings indicated that skeletal muscle-specific Fxr1 82- and 84-kD proteins are required for maintaining alignment and organization of Z-lines, and that dysregulated translation of specific mRNAs involved in Z-line organization may underlie the myopathic phenotype.