STRA6 – Matthew-Wood syndrome

Biallelic loss-of-function and missense variants in the membrane receptor gene STRA6 cause Matthew-Wood syndrome, an autosomal recessive multisystem malformation disorder. Initial reports in 2007 identified truncating and splice-site mutations that predict premature stop codons in fetuses with clinical anophthalmia, pulmonary agenesis, diaphragmatic defects, cardiac malformations, duodenal stenosis, and intrauterine growth retardation (PMID:17503335).

Genetic studies have now documented 21 reported patients across at least 14 unrelated families, fulfilling criteria for a Definitive gene–disease relationship (PMID:19309693). The inheritance is strictly autosomal recessive, with compound heterozygotes or homozygotes for STRA6 variants in affected individuals. Segregation analysis demonstrated two adult siblings harboring the same homozygous STRA6 allele, concordant with disease status (PMID:19309693).

The variant spectrum includes missense changes (e.g., c.1964G>A (p.Arg655His)), frameshift mutations, splice-site alterations, and small indels distributed across the coding region. A representative pathogenic allele is c.1964G>A (p.Arg655His), which abolishes a critical retinol-binding site and impairs membrane trafficking.

Functional assays corroborate a loss-of-function mechanism: patient fibroblasts show absence of STRA6 protein or mislocalization, and >900 site-directed mutants identify an essential extracellular domain for retinol-binding (PMID:17273977). In vivo zebrafish models recapitulate ocular malformations upon retinoic acid synthesis inhibition and in p.Gly304Lys mutants, confirming that disrupted vitamin A uptake underlies the phenotype (PMID:21901792).

The phenotypic spectrum extends from lethal PDAC (pulmonary hypoplasia, diaphragmatic hernia, anophthalmia, cardiac defects) to surviving patients with bushy eyebrows, patent ductus arteriosus, and normal early development. Common features include:

• Anophthalmia/microphthalmia (HP:0000528)
• Bushy ("thick") eyebrows (HP:0000574)
• Patent ductus arteriosus (HP:0001643)
• Cardiac malformations (HP:0001627)
• Pulmonary hypoplasia or agenesis (HP:0002086)
• Congenital diaphragmatic hernia (HP:0000776)
• Dextrocardia (HP:0001651)
• Hydroureter (HP:0000072)
• Tetralogy of Fallot (HP:0001636)
• Intellectual disability (HP:0001249)
• Intrauterine growth retardation (HP:0001511)
• Duodenal stenosis (HP:0100867)

Clinical genetic testing for STRA6 should be considered in any patient with anophthalmia, especially when accompanied by pulmonary, diaphragmatic, or cardiac anomalies. Early molecular diagnosis informs reproductive counseling, guides perinatal palliative care planning, and allows anticipatory management of multiorgan involvement.

Key Take-Home: STRA6 variant analysis is critical for definitive diagnosis of Matthew-Wood syndrome and directly impacts genetic counseling and perinatal care strategies.

References

• American Journal of Human Genetics • 2007 • Matthew-Wood syndrome is caused by truncating mutations in the retinol-binding protein receptor gene STRA6. PMID:17503335
• American Journal of Human Genetics • 2007 • Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation. PMID:17273977
• Human Mutation • 2009 • Phenotypic spectrum of STRA6 mutations: from Matthew-Wood syndrome to non-lethal anophthalmia. PMID:19309693
• Human Mutation • 2011 • First implication of STRA6 mutations in isolated anophthalmia, microphthalmia, and coloboma: a new dimension to the STRA6 phenotype. PMID:21901792
• American Journal of Medical Genetics Part A • 2009 • Pulmonary hypoplasia-diaphragmatic hernia-anophthalmia-cardiac defect (PDAC) syndrome due to STRA6 mutations--what are the minimal criteria? PMID:19839040
• Journal of Genetic Counseling • 2024 • Perinatal palliative care for family with prenatal diagnosis of Matthew-Wood syndrome. PMID:37792875

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