Jul 2026· Science China Life Sciences· 0 citations· 29 references
Medicine
TL;DR
A large-scale trio approach substantially expands the genetic landscape of hypospadias, demonstrates the critical value of trio-based sequencing for improving diagnostic yield, and decisively implicates ciliary genes in its pathogenesis.
Abstract
Hypospadias is one of the most common birth defects in China and a key feature of differences in sex development (DSD), yet its genetic etiology remains largely unresolved. Current diagnostic approaches using DSD-targeted gene panels have a low rate of definitive diagnoses (5.5%), highlighting the need for more comprehensive genetic investigation. In this study, we performed next-generation sequencing (NGS) on the largest trio-based cohort of hypospadias to date, comprising 106 pediatric cases and their parents (92 trios). We achieved a definitive genetic diagnosis in 6.6% of patients, identifying pathogenic variants in canonical DSD genes such as AR, NR5A1 and WT1. By incorporating a broader spectrum of potentially clinically significant variants, we increased the overall genetic identification rate to 33.0% (35/106). Strikingly, trio analysis uncovered a significant burden of de novo loss-of-function (LoF) variants (2.2-fold enrichment, P=0.001), primarily driven by variants in genes associated with ciliopathies (10.35-fold, P=0.016), a previously underappreciated gene class in hypospadias. Furthermore, we identified and functionally validated two high-confidence risk genes, PRKCZ and HRNR, based on recurrent de novo variants. Functional assays confirmed that these variants disrupt key biological mechanisms, including cell proliferation, migration, and androgen signaling. Our large-scale trio approach substantially expands the genetic landscape of hypospadias, demonstrates the critical value of trio-based sequencing for improving diagnostic yield, and decisively implicates ciliary genes in its pathogenesis.
This work collected cases of HTX investigated by trio-based whole-exome (WES) and whole-genome sequencing (WGS) and performed detailed clinical and molecular characterization in seven children and fetuses from France and Vietnam and revealed significant phenotypic heterogeneity while highlighting strong genotype-phenotype correlations.
Thi Bich Tuyen Ho, Alicia Coudert, Thi Thuy Hang Do et al.· Clinical Genetics· 0 citations
A tiered, genotype-informed approach—combining HPLC/CE phenotyping, targeted molecular diagnostics, genetic modifier profiling, and periodic re-evaluation—optimizes diagnostic precision and guides individualized management across the thalassemia spectrum.
Ashraf T. Soliman, F. Alyafei, Nada Alaaraj et al.· Thalassemia Reports· 0 citations
This is the first study in Latin America to analyze PHEX variants, which is considered crucial for the generation of regional evidence to understand the genetic variability of HH and for leading specific targeted treatment.
S. Ávila, Sara Fernández, Maximiliano Zeballos et al.· American Journal of Medical...· 0 citations
Non-obstructive azoospermia (NOA) represents the most severe form of male infertility, and the pathogenesis in partial patients can be attributed to endocrine dysfunction or heritable genetic variants. Although the application of whole-exome sequencing (WES) has facilitated the identification of numerous pathogenic genes associated with NOA, the genetic etiology of a significant proportion of cases remains elusive. In this study, we identified an NOA patient carrying a novel variant in DMRTB1 (c.792-797del, p.265-266del). The variant was rare in public databases and predicted to be likely pathogenic according to the American College of Medical Genetics (ACMG) guidelines. Structural modeling performed by SWISS-MODEL revealed the localized structural perturbations within residues 254-266, which may induce functional alterations. Histological analysis (H&E staining) of the testicular tissue revealed a complete absence of mature sperm within the seminiferous tubules, which is consistent with the essential role of this gene demonstrated in Dmrt6 knockout mice. Our findings demonstrate that the identified DMRTB1 variant is closely associated with the pathogenesis of NOA, thereby providing valuable genetic evidence for the diagnosis of NOA.
Yu-Hang Li, Shuai Lu, Xun Wang et al.· Clinical Genetics· 0 citations
Importance: Understanding population differences in epidemiology, clinical presentation, and genetic architecture remains a major challenge for all rare genetic disorders. Hirschsprung disease (HSCR), despite being the commonest cause of neonatal intestinal obstruction, has been poorly studied with respect to its significant heterogeneity across U.S. populations. Objective: To characterize self-identified race and ethnicity differences in HSCR incidence, clinical presentation, and genetic architecture in the United States from diverse data sources. Design, Setting, and Participants: We used retrospective, population-based surveillance data from 3 independent US wide sources - (1) The National Birth Defects Prevention Network (NBDPN; 1996-2010), (2) aggregated electronic health record data from Epic COSMOS (1997-2025), and (3) individual level clinical and genomic data from the Hirschsprung Disease Research Collaborative (HDRC; 2011-2025). Statistical analyses of incident HSCR cases identified at birth, across time and geography, in conjunction with clinical phenotypes and genome sequences from unrelated HDRC probands were performed to characterize epidemiologic, phenotypic and genetic heterogeneity in HSCR. Exposures: HSCR cases were identified based on standardized clinical diagnostic criteria, primarily rectal biopsy with histopathologic confirmation of aganglionosis. The disease was defined using ICD-9-CM code 751.3, CDC/BPA code 751.30-751.34. and ICD-10-CM code Q43.1. Patients were classified by self-identified race and ethnicity (SIRE), with primary comparisons conducted between non-Hispanic Blacks/African Americans (Blacks) and non-Hispanic Whites (Whites). Main Outcomes and Measures: HSCR incidence and the frequency of clinical features were estimated overall and by SIRE. We also estimated the individual and total genetic burden of rare pathogenic coding variants and common noncoding regulatory variants at established HSCR genes by population. Results: Overall HSCR incidence in the U.S. was 2.04 per 10,000 live births (95% CI, 1.99-2.09) as previously estimated. We show, Blacks have the highest HSCR incidence (2.83-3.13 per 10 000 live births), in comparison to Whites (1.89-2.02) and Asians (1.54-1.98), a difference not previously ascertained from previous smaller cohorts from limited geographical regions. This difference persists across surveillance times and geography. This incidence difference from NBDPN is consistent with Epic COSMOS, a nation-wide, independent hospital-based data source. Clinically, Blacks are more likely to present with isolated HSCR and with milder manifestations at birth, including chronic severe constipation (CSC). Genetically, the burden of pathogenic coding variants did not differ between Blacks and Whites. However, Blacks had a significantly higher enrichment of two non-coding regulatory variants (rs199582499 and rs28735659) at the SOX10 gene locus, as compared with Whites. Conclusions and Relevance: This study demonstrates, for the first time, that Black HSCR patients in the U.S. have a higher incidence accompanied by milder clinical presentation and distinct noncoding regulatory SOX10 variants as compared to White patients. Nevertheless, Blacks are severely under-represented in U.S. studies of HSCR leading to significant health disparities in their care and management.
M. Fu, H. Berk-Rauch, M. Erazo et al.· medRxiv· 0 citations
The 46,XY differences of sex development (DSD) represent a rare group of conditions arising from discordance between chromosomal and phenotypic sex. In cases of complete 46,XY gonadal dysgenesis (GD), the absence of testicular differentiation results in hypergonadotropic hypogonadism and preserved Müllerian structures. These patients face a substantial risk of developing gonadal malignancies, necessitating early identification and management. We describe the clinical, biochemical, and molecular profiles of four pediatric patients with 46,XY DSD of distinct etiologies, aiming to highlight the diagnostic challenges and the necessity of multifaceted long-term management strategies.
Four patients with complete 46,XY GD were included. Molecular analysis identified pathogenic variants in three cases: one WT1 splice-site variant (c.1432+4C>T) and two SRY variants (p.Arg30Ile and p.Glu89Argfs*15). The fourth patient was diagnosed based on clinical and biochemical criteria without an identified genetic variant. Gonadal malignancy was confirmed in 75% of cases (n = 3), including bilateral gonadoblastoma and mixed germ cell tumor. All patients underwent bilateral gonadectomy and subsequent pubertal induction (ages 12-16). At the latest follow-up (ages 16-21), full pubertal development and menarche were achieved in 100% of cases, with bone mineral density maintained within age-matched norms (Z-score: −0.3 to −1.7). Late diagnosis in the SRY group was associated with final heights significantly exceeding target height (up to +1.89 SD).
This case series underscores the marked phenotypic and genetic heterogeneity of 46,XY gonadal dysgenesis and the high prevalence of early-onset malignancy (75%). Precise molecular diagnosis is important for timely tumor risk stratification, guiding the timing of prophylactic gonadectomy and optimizing pubertal induction to prevent excessive final height. A proactive, multidisciplinary approach is essential to safeguard bone health and ensure long-term psychosocial well-being in these complex DSD patients.Table 1Clinical, genetic, and endocrine characteristics of four patients with 46,XY differences of sex development (DSD).FeaturesCase 1Case 2Case 3Case 4Age at diagnosis/ presentation11 y (SRNS since 4 y)Neonatal period (Turner work-up)6 y (precocious pubertal signs)16 y (post-tumor resection)Genetic findingWT1 (NM_000378.6): c.1432+4C>T (splice-site)None identifiedSRY(NM_003140.3)c.89G>T, p.Arg30Ile (exon 1)SRY (NM_003140.3)c.264dup, p.Glu89Argfs*15Main diagnosisWT1 (heterozygous splice-site variant, not Frasier-associated)Frasier syndrome (46,XY DSD + CKD)Complete 46,XY gonadal dysgenesis (Swyer)Complete 46,XY gonadal dysgenesis (Swyer)Age at gonadectomy13 y (bilateral)1 y (bilateral)6 y (bilateral)16-17 y (right tumor, left streak gonad)
B. T. D. Tavares da Silva, Miguel Saraiva, Catarina Figueiredo et al.· European Journal of Endocrin...· 0 citations
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