Survey of disorders of sex development in a large cohort of patients with diverse Mendelian phenotypes

Abualsaud, Dalia; Hashem, Mais; Alhashem, Amal; Alkuraya, Fowzan S.

doi:10.1002/ajmg.a.61876

Cited by 8 publications

(6 citation statements)

References 44 publications

(40 reference statements)

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“…The highest diagnostic yield was the syndromic 46, XY DSD subgroup where 69.2% (27/39) carried P/LP variants and 20.5% (8/39) carried VUS/LB/B variants. The overall diagnostic yield is similar to that reported recently in other large cohorts using a WES approach but higher than studies using an NGS gene panel (Baxter et al, 2015;Eggers et al, 2016;Kim et al, 2017;Ozen et al, 2017;Buonocore et al, 2019;Hughes et al, 2019;Xu et al, 2019;Abualsaud et al, 2020;Yu et al, 2021). Abualsaud et al (2020) identified a genetic cause in 51% of a cohort of 149 DSD cases, using targeted DSD gene panel Yu et al ( 2021) reported a diagnostic yield of 42.5% in 46, XY DSD whereas Xu et al (2019) reported a diagnostic yield of 46.9% of 46, XY DSD and 10.3% of DSD 46, XX individuals.…”

Section: Discussionsupporting

confidence: 86%

“…The overall diagnostic yield is similar to that reported recently in other large cohorts using a WES approach but higher than studies using an NGS gene panel (Baxter et al, 2015;Eggers et al, 2016;Kim et al, 2017;Ozen et al, 2017;Buonocore et al, 2019;Hughes et al, 2019;Xu et al, 2019;Abualsaud et al, 2020;Yu et al, 2021). Abualsaud et al (2020) identified a genetic cause in 51% of a cohort of 149 DSD cases, using targeted DSD gene panel Yu et al ( 2021) reported a diagnostic yield of 42.5% in 46, XY DSD whereas Xu et al (2019) reported a diagnostic yield of 46.9% of 46, XY DSD and 10.3% of DSD 46, XX individuals. Selected samples without molecular causes were re-analysed by whole exome sequencing (WES) and the yield did not improve the diagnostic rate (Xu et al, 2019).…”

Section: Discussionsupporting

confidence: 86%

“…Targeted sequencing, using panels with selected DSD genes, is reported to have a diagnostic yield of between 30 and 47% in 46, XY DSD cases ( Buonocore et al, 2019 ; Hughes et al, 2019 ; Xu et al, 2019 ). Using only the WES approach, Abualsaud et al, 2020 , identified potentially causal genetic variants in 42 genes carried by 51% (76/149) of the patient cohort ( Abualsaud et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Novel Genomic Variants, Atypical Phenotypes and Evidence of a Digenic/Oligogenic Contribution to Disorders/Differences of Sex Development in a Large North African Cohort

et al. 2022

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In a majority of individuals with disorders/differences of sex development (DSD) a genetic etiology is often elusive. However, new genes causing DSD are routinely reported and using the unbiased genomic approaches, such as whole exome sequencing (WES) should result in an increased diagnostic yield. Here, we performed WES on a large cohort of 125 individuals all of Algerian origin, who presented with a wide range of DSD phenotypes. The study excluded individuals with congenital adrenal hypoplasia (CAH) or chromosomal DSD. Parental consanguinity was reported in 36% of individuals. The genetic etiology was established in 49.6% (62/125) individuals of the total cohort, which includes 42.2% (35/83) of 46, XY non-syndromic DSD and 69.2% (27/39) of 46, XY syndromic DSD. No pathogenic variants were identified in the 46, XX DSD cases (0/3). Variants in the AR, HSD17B3, NR5A1 and SRD5A2 genes were the most common causes of DSD. Other variants were identified in genes associated with congenital hypogonadotropic hypogonadism (CHH), including the CHD7 and PROKR2. Previously unreported pathogenic/likely pathogenic variants (n = 30) involving 25 different genes were identified in 22.4% of the cohort. Remarkably 11.5% of the 46, XY DSD group carried variants classified as pathogenic/likely pathogenic variant in more than one gene known to cause DSD. The data indicates that variants in PLXNA3, a candidate CHH gene, is unlikely to be involved in CHH. The data also suggest that NR2F2 variants may cause 46, XY DSD.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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Novel Genomic Variants, Atypical Phenotypes and Evidence of a Digenic/Oligogenic Contribution to Disorders/Differences of Sex Development in a Large North African Cohort

et al. 2022

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“…Both affected siblings described herein display structural brain anomalies including mild to moderate cerebral volume loss, mild to moderate cerebellar vermian hypoplasia, variable degrees of thinning of the corpus callosum, and abnormal myelination for age on brain MRI, whereas abnormalities on brain MRI in the form of nonspecific arachnoid granulation were observed in only one out of the three affected individuals with brain imaging in Monies et al (2019). Interestingly, bilateral undescended testes observed in the male proband has been recently described in three (out of six) males from the two previously reported families with MRT71 in a follow‐up study on disorders of sex development (Abualsaud et al, 2020).…”

Section: Discussionmentioning

confidence: 81%

Neurodevelopmental disorder in an Egyptian family with a biallelic ALKBH8 variant

Saad

Marafi

Mitani

et al. 2021

American J of Med Genetics Pt A

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Alkylated DNA repair protein AlkB homolog 8 (ALKBH8) is a member of the AlkB family of dioxygenases. ALKBH8 is a methyltransferase of the highly variable wobble nucleoside position in the anticodon loop of tRNA and thus plays a critical role in tRNA modification by preserving codon recognition and preventing errors in amino acid incorporation during translation. Moreover, its activity catalyzes uridine modifications that are proposed to be critical for accurate protein translation. Previously, two distinct homozygous truncating variants in the final exon of ALKBH8 were described in two unrelated large Saudi Arabian kindreds with intellectual developmental disorder and autosomal recessive 71 (MRT71) syndrome (MIM# 618504). Here, we report a third family—of Egyptian descent—harboring a novel homozygous frame‐shift variant in the last exon of ALKBH8. Two affected siblings in this family exhibit global developmental delay and intellectual disability as shared characteristic features of MRT71 syndrome, and we further characterize their observed dysmorphic features and brain MRI findings. This description of a third family with a truncating ALKBH8 variant from a distinct population broadens the phenotypic and genotypic spectrum of MRT71 syndrome, affirms that perturbations in tRNA biogenesis can contribute to neurogenetic disease traits, and firmly establishes ALKBH8 as a novel neurodevelopmental disease gene.

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“…Recently, a study of a large cohort of patients with sex development disorders revealed that a mutation at the USP2 locus [c.550G4A:p. (Gly184Arg)] was associated with undescended testes with hypoplastic scrotum [ 126 , 158 ]. However, the cause of the phenotypic differences observed between Usp2 KO mice and human patients with mutations in the USP2 gene has not yet been elucidated.…”

Section: Male Genital Tractmentioning

confidence: 99%

USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes

Kitamura

Hashimoto

2021

IJMS

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Ubiquitin specific protease (USP) 2 is a multifunctional deubiquitinating enzyme. USP2 modulates cell cycle progression, and therefore carcinogenesis, via the deubiquitination of cyclins and Aurora-A. Other tumorigenic molecules, including epidermal growth factor and fatty acid synthase, are also targets for USP2. USP2 additionally prevents p53 signaling. On the other hand, USP2 functions as a key component of the CLOCK/BMAL1 complex and participates in rhythmic gene expression in the suprachiasmatic nucleus and liver. USP2 variants influence energy metabolism by controlling hepatic gluconeogenesis, hepatic cholesterol uptake, adipose tissue inflammation, and subsequent systemic insulin sensitivity. USP2 also has the potential to promote surface expression of ion channels in renal and intestinal epithelial cells. In addition to modifying the production of cytokines in immune cells, USP2 also modulates the signaling molecules that are involved in cytokine signaling in the target cells. Usp2 knockout mice exhibit changes in locomotion and male fertility, which suggest roles for USP2 in the central nervous system and male genital tract, respectively. In this review, we summarize the cellular events with USP2 contributions and list the signaling molecules that are upstream or downstream of USP2. Additionally, we describe phenotypic differences found in the in vitro and in vivo experimental models.

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Survey of disorders of sex development in a large cohort of patients with diverse Mendelian phenotypes

Cited by 8 publications

References 44 publications

Novel Genomic Variants, Atypical Phenotypes and Evidence of a Digenic/Oligogenic Contribution to Disorders/Differences of Sex Development in a Large North African Cohort

Novel Genomic Variants, Atypical Phenotypes and Evidence of a Digenic/Oligogenic Contribution to Disorders/Differences of Sex Development in a Large North African Cohort

Neurodevelopmental disorder in an Egyptian family with a biallelic ALKBH8 variant

USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes

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