A Homozygous Missense Variant in Hedgehog Acyltransferase (<b><i>HHAT</i></b>) Gene Associated with 46,XY Gonadal Dysgenesis

Abstract

<b><i>Introduction:</i></b> Disorders of gonadal development represent a clinically and genetically heterogeneous group of DSD, and the etiology in many cases remains unknown, indicating that our knowledge of factors controlling sex determination is still limited. <b><i>Methods:</i></b> We describe a 46,XY DSD patient from Egypt. The patient was reared as female, born to consanguineous parents, and was referred to us at the age of 5 years because of ambiguous genitalia. On examination, the girl was microcephalic (head circumference –3 SD), but her height and weight were normal for her age and sex. <b><i>Results:</i></b> Exome sequencing identified a homozygous variant in the hedgehog acyltransferase (<i>HHAT</i>) gene, which encodes an enzyme that is required for multimerization and signaling potency of the hedgehog secreted proteins. The variant is a novel homozygous missense change c.1329C&#x3e;A (p.N443K), located within transmembrane domain 9, which segregated with the phenotype in the family. <b><i>Discussion/Conclusion:</i></b> Our results expand the phenotypic spectrum associated with <i>HHAT</i> variants to include 46,XY gonadal dysgenesis and reinforce the role of exome sequencing in unraveling new genes that play a pivotal role in sexual development.