NHS – Nance-Horan syndrome

Nance-Horan syndrome (NHS) is a rare X-linked developmental disorder characterized by bilateral congenital cataracts, microcornea, dental anomalies and variable intellectual disability. Affected males typically present dense congenital central cataracts, microphthalmia, anteverted pinnae, brachymetacarpalia and screwdriver-shaped incisors, while heterozygous females manifest milder lens opacities and dental dysmorphism (PMID:19941417). The disease locus maps to Xp22.13 and is caused by pathogenic variants in the NHS gene (NHS).

Inheritance is X-linked, with segregation of pathogenic NHS alleles in over 30 independent families and more than 100 affected individuals (PMID:17417607). Truncating, splice-site and microdeletion variants predominate, leading to protein loss of function. In a Chinese pedigree, a nonsense variant c.322G>T (p.Glu108Ter) co-segregated with NHS in multiple affected males and carrier females (PMID:25091991).

Segregation analyses across kindreds demonstrate co-segregation of NHS variants with disease in 11 additional affected relatives, reinforcing a highly penetrant X-linked pattern. Variant spectrum includes nonsense (e.g., c.322G>T (p.Glu108Ter)), frameshift (e.g., c.558insA (p.Glu186GlufsTer11)), splice-site and multi-exon deletions. Recurrent truncations (e.g., p.Arg394Ter) and rare founder alleles have been reported across populations.

Functional studies indicate that the NHS-A isoform localizes to epithelial tight junctions, co-localizing with ZO-1 in lens epithelium, and that NHS knockdown disrupts the circumferential actin ring and lamellipod formation (PMID:16675532; PMID:20332100). Loss of NHS disrupts cell-cell junction integrity, providing a mechanistic basis for congenital cataractogenesis.

No studies have refuted the gene-disease relationship or identified alternative genetic etiologies in patients meeting NHS diagnostic criteria. X-linked cataract phenotypes without NHS coding mutations have been attributed to copy number changes affecting NHS regulatory elements, confirming allelism between congenital cataract and NHS (PMID:19414485).

Integration of robust genetic segregation, diverse loss-of-function variants and concordant functional data establishes a definitive association between NHS and Nance-Horan syndrome. NHS genetic testing informs clinical diagnosis, guides genetic counseling and enables early intervention for cataract extraction and dental management.

Key take-home: Pathogenic NHS loss-of-function variants cause a definitive X-linked syndrome, and genetic testing is essential for diagnosis and family planning.

References

• Ophthalmic genetics | 2009 | Ophthalmic pathology of Nance-Horan syndrome: case report and review of the literature. PMID:19941417
• Molecular vision | 2007 | Identification of three novel NHS mutations in families with Nance-Horan syndrome. PMID:17417607
• Human molecular genetics | 2006 | Nance-Horan syndrome protein, NHS, associates with epithelial cell junctions. PMID:16675532
• Human molecular genetics | 2010 | The Nance-Horan syndrome protein encodes a functional WAVE homology domain (WHD) and is important for co-ordinating actin remodelling and maintaining cell morphology. PMID:20332100
• Journal of Zhejiang University. Science. B | 2014 | Identification of a novel mutation in a Chinese family with Nance-Horan syndrome by whole exome sequencing. PMID:25091991
• Human molecular genetics | 2009 | X-linked cataract and Nance-Horan syndrome are allelic disorders. PMID:19414485

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