ATP7A – Occipital Horn Syndrome

Occipital Horn Syndrome (OHS) is a mild allelic variant of Menkes disease characterized by connective tissue abnormalities, skeletal exostoses, and bladder diverticula. OHS arises from hemizygous mutations in ATP7A, a copper‐transporting P-type ATPase localized to the trans-Golgi network in normal cells. Dysfunctional ATP7A impairs copper delivery to lysyl oxidase, leading to defective collagen crosslinking and resultant connective tissue phenotypes.

Genetic evidence supports an X-linked recessive inheritance mode for OHS. Over 58 unrelated families with OHS have been molecularly characterized, revealing a spectrum of ATP7A mutations including nonsense, splice-site, missense, deep intronic, and retrotransposon insertions (PMID:10463276). In one family, a novel nonsense variant c.4222A>T (p.Lys1408Ter) segregated with OHS in multiple males (PMID:28761814). A deep intronic variant in exon 5 was identified in four affected males exhibiting variable skeletal and gastrointestinal phenotypes (PMID:38141875), and a recent report described an SVA_D retrotransposon insertion causing aberrant splicing in a single OHS patient (PMID:38960580).

Segregation analyses in OHS families demonstrate segregation of pathogenic ATP7A alleles in at least 4 additional affected relatives beyond probands (PMID:28761814). Founder and recurrent variants have not been widely reported, consistent with private mutations across diverse populations. Carrier screening in at-risk females enables prenatal diagnosis and early management.

Functional studies corroborate the pathogenicity of ATP7A variants in OHS. Constitutive skipping of exon 10 yields an in‐frame deletion of transmembrane domains 3 and 4 and mislocalizes the protein to the endoplasmic reticulum instead of the Golgi apparatus (PMID:9467005). Antisense oligonucleotide (AO) correction of a retrotransposon-induced splice donor site restored normal ATP7A transcripts and copper transport in patient fibroblasts (PMID:38960580). These assays provide concordant experimental evidence linking defective ATP7A localization and splicing to OHS phenotypes.

Integration of genetic and functional data supports a Strong gene–disease association for ATP7A and OHS. The combination of X-linked inheritance, segregation in multiple families, a broad variant spectrum, and mechanistic in vitro rescue studies fulfills ClinGen criteria for a Strong classification. Key take-home: ATP7A variant analysis is critical for definitive diagnosis of OHS, guiding carrier testing, prenatal screening, and informing potential splice-modulating therapies.

References

• Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society • 1998 • Metabolic and molecular bases of Menkes disease and occipital horn syndrome. PMID:10463276
• Molecular genetics and metabolism reports • 2017 • A novel nonsense ATP7A pathogenic variant in a family exhibiting a variable occipital horn syndrome phenotype. PMID:28761814
• European journal of medical genetics • 2024 • Deep intronic variant causes aberrant splicing of ATP7A in a family with a variable occipital horn syndrome phenotype. PMID:38141875
• Journal of medical genetics • 2024 • Long-read sequencing identifies an SVA_D retrotransposon insertion deep within the intron of ATP7A as a novel cause of occipital horn syndrome. PMID:38960580
• Human molecular genetics • 1998 • Similar splice-site mutations of the ATP7A gene lead to different phenotypes: classical Menkes disease or occipital horn syndrome. PMID:9467005

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