Nance-Horan syndrome pedigree due to a novel microdeletion and skewed X chromosome inactivation

Background: Nance-Horan syndrome (NHS) is a rare and often overlooked X-linked dominant disorder characterized by dense congenital cataracts, dental abnormalities, and mental retardation. The majority of NHS variations include frameshift mutations, nonsense mutations, microdeletions, and insertions. Methods: Copy number variation sequencing was performed to determine the microdeletion. The expression of NHS was detected by RT-PCR. Four family members were tested for X chromosome inactivation. Results: In this study, all members were examined for systemic examinations and genetic testing of four members and two affected subjects are observed. We identified a heterozygous microdeletion of -0.52 Mb at Xp22.13 in a female proband presenting NHS phenotypically. The microdeletion contains the REPS2 and NHS genes and was inherited from a phenotypically normal mother. Of interest, the expression NHS of proband was reduced and the skewed X chromosome inactivation rate reached more than 85% compared with her mother and the control. It was concluded that the haploinsufficiency of the NHS gene may account for the majority of clinical symptoms in the affected subjects. The variability among female carriers presumably results from nonrandom X chromosome inactivation. Conclusion: Our findings broaden the spectrum of NHS mutations and provide molecular insight into NHS clinical prenatal genetic diagnosis.