NHS was first reported in relation to X-linked Nance-Horan syndrome in 2003 (Burdon et al., PMID: 14564667). NHS encodes a protein that is essential for normal embryonic development and acts as a regulator of actin remodeling. Nance-Horan syndrome is characterized by congenital cataracts with microcornea, dental abnormalities, facial dysmorphism, and in some patients, intellectual disability and autism spectrum disorder. Female carriers may be asymptomatic or exhibit milder features, such as lens opacities, mild facial dysmorphism, and characteristic dental abnormalities.
Five variants (nonsense, frameshift, splice) that have been reported in six probands in two publications (PMIDs: 14564667, 18949062) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by a mouse model with cataracts (PMID: 16357105) and functional alterations in non-patient cells (PMID: 20332100).
In summary, there is definitive evidence supporting the relationship between NHS and X-linked Nance-Horan syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 20, 2017 (SOP Version 5). As of July 2022, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 9. No new evidence has been added.
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