A Homozygous Missense Variant in Hedgehog Acyltransferase (HHAT) 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>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.

Muscle spasms as presenting feature of Nivelon‐Nivelon‐Mabile syndrome

“…The proband was concluded to be affected with HHAT gene‐associated NNMS in view of these results and concordance with previously reported phenotype of this condition (Abdel‐Salam et al, 2019; Callier et al, 2014; Mazen et al, 2022; Pande et al, 2021).…”

“…Also, this substitution disrupts a salt-bridge (hydrogen bond) formed by OD1 atom of Asp314 and NH2 atom of Arg93 (distance: 3.858 Å) (Figure5b,c). These alterations might potentially result in a change to the protein's structure and function as interpreted by VarSite and Missense3D.The proband was concluded to be affected with HHAT geneassociated NNMS in view of these results and concordance with previously reported phenotype of this condition(Abdel-Salam et al, 2019;Callier et al, 2014;Mazen et al, 2022;Pande et al, 2021).…”

“…In contrast, this patient had simplified gyration which was not reported in previous individuals. Sex reversal and genital ambiguity has been reported in 46,XY individuals with biallelic HHAT variants (Mazen et al, 2022; Nivelon et al, 1992; Pande et al, 2021), while our patient and others with 46,XX karyotype have normal reproductive fitness. The clinical and other relevant findings of all patients with biallelic HHAT variants have been depicted in Table 1.…”

“…Third family comprised of two fetuses and one living proband in which severe microphthalmia, microcephaly, holoprosencephaly in one fetus, skeletal dysplasia, facial dysmorphism, and sex reversal were reported (Pande et al, 2021). Another recently reported patient presented with genital ambiguity and microcephaly with no other obvious abnormalities (Mazen et al, 2022).…”