A novel <i>HSD17B3</i> gene mutation in a 46,XY female‐phenotype newborn identified by whole‐exome sequencing

Bertalan, Rita; Admoni, Osnat; Bashamboo, Anu; Tenenbaum‐Rakover, Yardena; McElreavey, Kenneth

doi:10.1111/cen.13396

Cited by 2 publications

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“…Sequencing of candidate genes, including SRD5A2, LHR, AR and GPR54 , was negative for pathogenic variants. WES performed at the age of 8 years revealed a novel missense variant of the HSD17B3 gene previously reported by us ( 13 ). The parents were heterozygous for the identified mutation.…”

Section: Resultssupporting

confidence: 61%

The evolving role of whole-exome sequencing in the management of disorders of sex development

Tenenbaum‐Rakover

Admoni

Elias-Assad

et al. 2021

Endocrine Connections

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Objective: Disorders of sex development (DSD) are defined as congenital conditions in which development of chromosomal, gonadal and anatomical sex is atypical. Despite wide laboratory and imaging investigations, the etiology of DSD is unknown in over 50% of patients. Methods: We evaluated the etiology of DSD by whole-exome sequencing (WES) at a mean age of 10 years in nine patients for whom extensive evaluation, including hormonal, imaging and candidate gene approaches, had not identified an etiology. Results: The eight 46,XY patients presented with micropenis, cryptorchidism and hypospadias at birth and the 46,XX patient presented with labia majora fusion. In seven patients (78%), pathogenic variants were identified for RXFP2, HSD17B3, WT1, BMP4, POR, CHD7 and SIN3A. In two patients, no causative variants were found. Mutations in three genes were reported previously with different phenotypes: an 11-year-old boy with a novel de novo variant in BMP4; such variants are mainly associated with microphthalmia and in few cases with external genitalia anomalies in males, supporting the role of BMP4 in the development of male external genitalia; a 12-year-old boy with a known pathogenic variant in RXFP2, encoding insulin-like 3 hormone receptor, and previously reported in adult men with cryptorchidism; an 8-year-old boy with syndromic DSD had a de novo deletion in SIN3A. Conclusions: Our findings of molecular etiologies for DSD in 78% of our patients indicate a major role for WES in early DSD diagnosis and management, and highlights the importance of rapid molecular diagnosis in early infancy for sex of rearing decisions.

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Section: Resultssupporting

confidence: 61%

The evolving role of whole-exome sequencing in the management of disorders of sex development

Tenenbaum‐Rakover

Admoni

Elias-Assad

et al. 2021

Endocrine Connections

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“…Sixty-eight articles reported one or more patients with HSD17B3 mutations ( Supplemental Table S1 ) [ 1 , 3 , 4 , 5 , 9 , 10 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ...…”

Section: Resultsmentioning

confidence: 99%

Disorder of Sex Development Due to 17-Beta-Hydroxysteroid Dehydrogenase Type 3 Deficiency: A Case Report and Review of 70 Different HSD17B3 Mutations Reported in 239 Patients

Gonçalves

Carriço

Bastos

et al. 2022

IJMS

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The 17-beta-hydroxysteroid dehydrogenase type 3 (17-β-HSD3) enzyme converts androstenedione to testosterone and is encoded by the HSD17B3 gene. Homozygous or compound heterozygous HSD17B3 mutations block the synthesis of testosterone in the fetal testis, resulting in a Disorder of Sex Development (DSD). We describe a child raised as a female in whom the discovery of testes in the inguinal canals led to a genetic study by whole exome sequencing (WES) and to the identification of a compound heterozygous mutation of the HSD17B3 gene (c.608C>T, p.Ala203Val, and c.645A>T, p.Glu215Asp). Furthermore, we review all HSD17B3 mutations published so far in cases of 17-β-HSD3 deficiency. A total of 70 different HSD17B3 mutations have so far been reported in 239 patients from 187 families. A total of 118 families had homozygous mutations, 63 had compound heterozygous mutations and six had undetermined genotypes. Mutations occurred in all 11 exons and were missense (55%), splice-site (29%), small deletions and insertions (7%), nonsense (5%), and multiple exon deletions and duplications (2%). Several mutations were recurrent and missense mutations at codon 80 and the splice-site mutation c.277+4A>T each represented 17% of all mutated alleles. These findings may be useful to those involved in the clinical management and genetic diagnosis of this disorder.

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A novel HSD17B3 gene mutation in a 46,XY female‐phenotype newborn identified by whole‐exome sequencing

Cited by 2 publications

References 5 publications

The evolving role of whole-exome sequencing in the management of disorders of sex development

The evolving role of whole-exome sequencing in the management of disorders of sex development

Disorder of Sex Development Due to 17-Beta-Hydroxysteroid Dehydrogenase Type 3 Deficiency: A Case Report and Review of 70 Different HSD17B3 Mutations Reported in 239 Patients

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