Abstract
Nance–Horan syndrome (NHS) is a rare X-linked dominant disorder caused by mutation in the NHS gene on chromosome Xp22.13. (OMIM 302350). Classic NHS manifested in males is characterized by congenital cataracts, dental anomalies, dysmorphic facial features and occasionally intellectual disability. Females typically have a milder presentation. The majority of reported cases of NHS are the result of nonsense mutations and small deletions. Isolated X-linked congenital cataract is caused by non-recurrent rearrangement-associated aberrant NHS transcription. Classic NHS in females associated with gene disruption by balanced X-autosome translocation has been infrequently reported. We present a familial NHS associated with translocation t(X;19) (Xp22.13;q13.1). The proband, a 28-year-old female, presented with intellectual disability, dysmorphic features, short stature, primary amenorrhea, cleft palate, and horseshoe kidney, but no NHS phenotype. A karyotype and chromosome microarray analysis (CMA) revealed partial monosomy Xp/partial trisomy 19q with the breakpoint at Xp22.13 disrupting the NHS gene. Family history revealed congenital cataracts and glaucoma in the patient’s mother, and congenital cataracts in maternal half-sister and maternal grandmother. The same balanced translocation t(X;19) was subsequently identified in both the mother and maternal half-sister, and further clinical evaluation of the maternal half-sister made a diagnosis of NHS. This study describes the clinical implication of NHS gene disruption due to balanced X-autosome translocations as a unique mechanism causing Nance–Horan syndrome, refines dose effects of NHS on disease presentation and phenotype expressivity, and justifies consideration of karyotype and fluorescence in situ hybridization (FISH) analysis for female patients with familial NHS if single-gene analysis of NHS is negative.
Highlights
Nance–Horan syndrome (NHS), known as cataract-dental syndrome, is characterized by bilateral congenital cataracts, dental anomalies such as screwdriver-shaped teeth and bud molars, and dysmorphic facial features such as anteverted pinnae and broad nose [1,2,3]
We serendipitously identified X-autosome translocation-mediated disruption of the NHS gene by analyzing the genomic imbalance responsible for a proband’s phenotype of intellectual disability, multiple congenital anomalies, and primary amenorrhea
Chromosome analysis identified in the proband a derivative chromosome X resulted from an unbalanced translocation involving breakpoints on the short arm of chromosome X at band Xp22.1 and the long arm of chromosome 19 at band 19q13.1 (Fig. 2a). Array-comparative genomic hybridization (aCGH)-based chromosome microarray analysis (CMA) revealed a 17.3 Mb partial terminal monosomy Xp (Fig. 2b, 76 OMIM genes) and a 22.4 Mb partial terminal trisomy 19q (Fig. 2c, 599 OMIM genes), consistent with an unbalanced product of translocation t(X;19)
Summary
NHS, known as cataract-dental syndrome, is characterized by bilateral congenital cataracts, dental anomalies such as screwdriver-shaped teeth and bud molars, and dysmorphic facial features such as anteverted pinnae and broad nose [1,2,3]. NHS is inherited in an X-linked manner with heterozygous female carriers often presenting similar but Miller et al Mol Cytogenet (2021) 14:48 milder phenotypes than affected males [4, 5]. Female carriers typically display posterior Y-sutural lens opacities often with likely congenital cortical riders, but are not expected to have congenital cataracts [6]. The NHS gene encompasses ~ 650 kb of genomic DNA, coding for a 1630-amino acid putative protein. A search of The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff (http://www.hgmd.cf.ac.uk/) reveals fewer than 50 reported mutations in NHS. Isolated X-linked cataract with other anomalies is an allelic disorder due to altered NHS transcription [6, 9]
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