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Recessive Spondylocarpotarsal Synostosis Syndrome Due to Compound Heterozygosity for Variants in MYH3
- Source :
- American Journal of Human Genetics, 102(6), 1115. Cell Press, American Journal of Human Genetics, 102(6), 1115-1125. CELL PRESS, American Journal of Human Genetics, 102(6), 1115-1125. Cell Press
- Publication Year :
- 2018
-
Abstract
- Spondylocarpotarsal synostosis syndrome (SCTS) is characterized by intervertebral fusions and fusion of the carpal and tarsal bones. Biallelic mutations in FLNB cause this condition in some families, whereas monoallelic variants in MYH3, encoding embryonic heavy chain myosin 3, have been implicated in dominantly inherited forms of the disorder. Here, five individuals without FLNB mutations from three families were hypothesized to be affected by recessive SCTS on account of sibling recurrence of the phenotype. Initial whole-exome sequencing (WES) showed that all five were heterozygous for one of two independent splice-site variants in MYH3. Despite evidence indicating that three of the five individuals shared two allelic haplotypes encompassing MYH3, no second variant could be located in the WES datasets. Subsequent genome sequencing of these three individuals demonstrated a variant altering a 5' UTR splice donor site (rs557849165 in MYH3) not represented by exome-capture platforms. When the cohort was expanded to 16 SCTS-affected individuals without FLNB mutations, nine had truncating mutations transmitted by unaffected parents, and six inherited the rs557849165 variant in trans, an observation at odds with the population allele frequency for this variant. The rs557849165 variant disrupts splicing in the 5' UTR but is still permissive of MYH3 translational initiation, albeit with reduced efficiency. Although some MYH3 variants cause dominant SCTS, these data indicate that others (notably truncating variants) do not, except in the context of compound heterozygosity for a second hypomorphic allele. These observations make genetic diagnosis challenging in the context of simplex presentations of the disorder.
- Subjects :
- 0301 basic medicine
Male
SHELDON-HALL-SYNDROME
skeletal dysplasia
Compound heterozygosity
0302 clinical medicine
MYH3
FLNB
Musculoskeletal Diseases
INBREEDING COEFFICIENT
Exome sequencing
Genetics (clinical)
Genetics
education.field_of_study
SPONDYLOCARPOTARSAL SYNOSTOSIS SYNDROME
Lumbar Vertebrae
Published Erratum
Chromosome Mapping
Syndrome
CAUSE DISTAL ARTHROGRYPOSIS
Pedigree
Phenotype
Scoliosis
Synostosis
030220 oncology & carcinogenesis
Female
Heterozygote
Filamins
RNA Splicing
Population
SNP
Context (language use)
Genes, Recessive
Biology
Article
Thoracic Vertebrae
03 medical and health sciences
distal arthrogryposis type 8
filamin B
spondylocarpotarsal syndrome
Exome Sequencing
Humans
Abnormalities, Multiple
Allele
education
Allele frequency
Alleles
pondylocarpotarsal syndrome
SPECTRUM
Myosin Heavy Chains
MUTATIONS
Haplotype
Correction
Regret
GENE
Human genetics
030104 developmental biology
Haplotypes
Mutation
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 00029297
- Volume :
- 102
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- American Journal of Human Genetics
- Accession number :
- edsair.doi.dedup.....836c1f575f6bd54c57d61a339e68f235