Jul 2026· Genetics in Medicine· Vol 28, pp.
102642
· 1 citation
Medicine
TL;DR
This represents the most comprehensive characterization to date of TRND, a novel neurodevelopmental disorder, defining its genotypic and phenotypic spectrum.
Abstract
Purpose
TCF7L2 (OMIM:602228; HGNC:11641) is a transcription factor and critical effector of the Wnt/β-Catenin pathway. In 2021, 11 pediatric patients with mono-allelic predicted loss-of-function (pLOF) TCF7L2 variants and syndromic features were observed. Characterization of patients with pLOF TCF7L2 variants and neurodevelopmental features - herein referred to as TCF7L2-related neurodevelopmental disorder (TRND) - is urgently needed.
Methods
We leveraged multiple methods (GeneMatcher, DECIPHER, literature review, public/private repositories) to identify an international cohort of 76 patients with pLOF TCF7L2 variants and neurodevelopmental features and phenotypically characterized them. We also retrospectively searched for an independent cohort of adults with pLOF TCF7L2 variants (n = 11) from 60,000+ PennMedicine BioBank (PMBB) patients.
Results
Among 76 patients with pLOF TCF7L2 variants, speech delay (95.3%), craniofacial dysmorphisms (73.3%), ophthalmologic conditions (65.5%), autism (62.1%), and orthopedic abnormalities (52.6%) were most commonly observed. Phenotypic differences did not cluster by variant type or genomic locus. Among PMBB patients, an association of nominal significance with type 2 diabetes with renal manifestations (OR = 5.8; p-value = 0.03) was detected, warranting further investigation.
Conclusions
This represents the most comprehensive characterization to date of TRND, a novel neurodevelopmental disorder, defining its genotypic and phenotypic spectrum. We opened a Simons Searchlight natural history study (https://www.simonssearchlight.org/research/what-we-study/tcf7l2/) to enhance understanding of this condition.
To the authors' knowledge, this is the first report of such a unique overlap, highlighting the importance of considering multilocus genomic variation in heterogeneous neurodevelopmental presentations.
M. Cassone, A. Moschella, D. Mei et al.· Gene· 0 citations
PPP1R21-related neurodevelopmental disorder (PPP1R21-NDD) is an ultra-rare autosomal-recessive encephalopathy caused by dysfunction of the Five-subunit Endosomal Rab5 and RNA/ribosome intermediarY (FERRY) complex. To delineate the clinical, neuroimaging, and molecular spectrum of PPP1R21-NDD and outline diagnostic and research priorities. Targeted searches of PubMed, EMBASE, Scopus, Web of Science, and Google Scholar through January 2026 were performed. Eligible reports included molecularly confirmed biallelic PPP1R21 cases and related functional studies. Two researchers independently extracted individual-level data following narrative review quality criteria. Twenty-five individuals from 21 families harbored 17 distinct variants (15 loss-of-function, 2 missense), all homozygous, reflecting high consanguinity. Profound global developmental delay/intellectual disability was universal; hypotonia near-universal (22/25, 88%). Ambulation was delayed and ataxic when achieved; expressive language was minimal or absent. A recognizable coarse facial gestalt was observed with thick eyebrows, broad nasal bridge, thick lips, and low-set ears. Systemic features included feeding dysfunction and respiratory morbidity requiring gastrostomy or tracheostomy in severe cases. Mortality was 17% (4/24). Neuroimaging showed callosal thinning, white-matter volume loss, ventricular enlargement, and vermian hypoplasia. Patient fibroblasts showed delayed transferrin clearance and elevated proteasome activity, suggesting endosomal dysfunction and proteasome hyperactivation. PPP1R21-NDD is a severe recessive encephalopathy with a convergent phenotype and evidence of endo-lysosomal dysfunction. Diagnosis should be pursued with exome or genome sequencing in patients with characteristic clinical and neuroimaging features, particularly in consanguineous families. Research priorities include natural history studies, standardized magnetic resonance imaging (MRI) protocols, neural disease models, and therapeutic strategies targeting endosomal trafficking.
F. Comisi, G. Di Pasquale, A. Comisi et al.· Neurogenetics· 0 citations
BACKGROUND
Whole exome sequencing (WES) has improved diagnostic rates for neurodevelopmental disorders (NDDs) while introducing challenges in novel variant interpretation. DHX30-related NDD (DHX30-NDD) is a recently described condition with an evolving phenotypic spectrum.
OBJECTIVES
To expand the understanding of the DHX30-NDD genotype-phenotype spectrum by integrating a case-based WES interpretation with a scoping review.
METHODS
We performed comprehensive genetic analysis (karyotyping, microarray, WES) on a proband with global developmental delay (GDD). A systematic literature search of PubMed/MEDLINE, Scopus and Google Scholar from database inception to April 2026 identified 10 publications including 51 individuals with DHX30-NDD. Clinical and genetic data were extracted to characterize the genotype-phenotype spectrum.
RESULTS
The proband presented with GDD and right microtia, harbouring a de novo heterozygous pathogenic DHX30 missense variant (c.1478G > A; p.Arg493His), confirming DHX30-NDD. To our knowledge, this is the first reported individual with DHX30-NDD and microtia. The scoping review confirmed DHX30 variants are formed predominantly de novo and affected both sexes (22 males; 29 females). Hallmark manifestations were motor delay (50/51; 98.0%), GDD/ID (48/49; 98.0%), hypotonia (48/51; 94.1%), feeding difficulties (38/51; 74.5%), ataxia (17/23; 73.9%), abnormal brain imaging (36/49; 73.5%) and absent expressive language (35/48; 72.9%). Digital anomalies (31/51; 60.8%), eye anomalies (28/51; 54.9%), autistic behaviours (24/44; 54.5%), sleep disturbances (26/51; 51.0%), joint hypermobility (25/51; 49.0%), microcephaly (23/51; 45.1%) and ear anomalies (22/51; 43.1%) were also frequent.
CONCLUSIONS
This study potentially expands the phenotypic spectrum of DHX30-NDD, highlights the clinical utility of WES for diagnosing GDD and underscores the importance of ongoing WES reanalysis for evolving variant interpretation.
Nattaporn Tassanakijpanich, Areerat Hnoonual, Oradawan Plong-On et al.· Journal of Intellectual Disa...· 0 citations
Background/aim Cryptorchidism is the most common congenital anomaly of the male genitourinary system, characterized by a multifactorial etiology. The disheveled-associated activator of morphogenesis 2 (DAAM2) gene regulates androgen receptor (AR)-dependent transcription; its variants are associated with partial androgen insensitivity. Since the inguinoscrotal phase of testicular descent is androgen-dependent, we hypothesized that DAAM2 variants contribute to cryptorchidism susceptibility. This pilot study, designed to generate hypotheses rather than to establish association, investigated the frequency of two functionally characterized DAAM2 variants, p.(Asp165Glu) and p.(Asn614ThrfsTer2), in pediatric cryptorchidism. Materials and methods This prospective case-control study included 40 male pediatric cryptorchidism patients and 39 age- and sex-matched healthy male controls. Genomic DNA was extracted from peripheral blood. The p.(Asp165Glu) variant was genotyped by TaqMan allelic discrimination and p.(Asn614ThrfsTer2) by ARMS-PCR with melting curve analysis. Genotype distributions were compared using linear-by-linear association testing with exact p-values, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by binary logistic regression. Results Heterozygous p.N614Tfs*2 carriage was more frequent in cryptorchidism patients (12.5%, n = 5) than in controls (2.6%, n = 1), with an unadjusted OR of 5.43 (95% CI: 0.6048.78, p = 0.131). Heterozygous p.D165E frequency was similar in both groups (7.5% vs. 7.7%; OR: 1.03, 95% CI: 0.19–5.45, p = 0.974), whereas homozygous p.D165E was identified exclusively in 2 of 40 cryptorchidism patients (5.0%) and in none of the controls, resulting in complete separation in the regression model. Conclusion Although statistical significance could not be reached due to the limited size of the study group, the observed fivefold increase in heterozygosity of p.(Asn614ThrfsTer2) and the presence of homozygosity of p.(Asp165Glu) in cryptorchidism cases contribute to the literature. These data suggest that DAAM2 variants may play a potential role in the etiology of cryptorchidism.
Onur Yalçın, Çağrı Doğan· Turkish Journal of Medical S...· 0 citations
This study contributes additional cases to the expanding phenotypic and mutational spectrum of ZNF292-related neurodevelopmental disorder and indicates growth retardation was observed in all eight individuals, but given the limitations of a single-center referral cohort, this observation should be interpreted with caution and requires validation in larger studies.
Yaping Shen, R. Pan, Chen Liu et al.· Genes· 0 citations
Background Global developmental delay (GDD)/intellectual disability (ID) represent a group of neurodevelopmental disorders (NDDs) with onset in childhood with a global prevalence of 1–3%. The etiology of GDD/ID is complex, with genetic factors accounting for about half of cases. Exome sequencing (ES) has proven to be an effective diagnostic tool for genetically heterogeneous disorders such as GDD/ID. This study aims to identify the genetic etiologies using ES in a Chinese patient with NDD. Methods Clinical data were collected through physical examination. Trio-ES was conducted to investigate the potential genetic causes, followed by Sanger sequencing for validation. Results The proband exhibited facial dysmorphisms, motor and language development delay, ID, autism spectrum disorder, and attention-deficit hyperactivity disorder symptoms. Trio-ES identified a novel maternal inherited hemizygous nonsense variant c.205G>T (p.E69*) in ZNF711, and a novel de novo missense variant c.673C>T (p.R225C) in SRCAP. Both of variants were classified as likely pathogenic. Phenotype dissection revealed ZNF711 dominated neurodevelopmental abnormalities (Intellectual developmental disorder, X-linked 97, XLID97) and SRCAP contributed to multisystemic manifestations (developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities, DEHMBA). Conclusion To our knowledge, this study reports the first case of concurrent ZNF711 and SRCAP variants in China, expanding variant spectrum of both genes. It highlights the critical value of ES for detecting multi-gene variants in probands with complex phenotypes.
Ting-Ting Liu, Ming-Tao Huang, Min Dai et al.· The Application of Clinical...· 0 citations
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