Aug 2026· Gene· Vol 1012, pp.
150353
· 0 citations· 21 references
Medicine
TL;DR
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.
Abstract
We report a unique clinical case of a male child presenting with a blended phenotype characterized by intellectual disability, seizures, periventricular nodular heterotopia (PVNH), congenital central hypothyroidism, and multiorgan malformations. Exome sequencing (ES) identified three rare variants: a de novo frameshift variant in SETD5 (g.3-9441593 ;NM_001080517.3:c.812dup; p.(Leu271PhefsTer42)), a de novo missense variant in the WW domain of NEDD4L (NM_015277.6:c.1525C > T; p.(Arg529Cys)), and a maternally inherited nonsense variant in TBL1X (X-9711651-C-T) (NM_005647.4:c.1480C > T; p.(Arg494Ter)). While the likely pathogenic SETD5 and TBL1X variants are consistent with the neurodevelopmental delay and central hypothyroidism respectively, the NEDD4L variant of uncertain significance (VUS) represents a plausible candidate for the PVNH. To our knowledge, this is the first report of such a unique overlap, highlighting the importance of considering multilocus genomic variation in heterogeneous neurodevelopmental presentations.
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, Rongrong Pan, Chen Liu et al.· Genes· 0 citations
Background Phenotypic variability in PTEN hamartoma tumor syndrome (PHTS) remains incompletely understood, and the contribution of additional rare genetic variants has rarely been functionally investigated. Case presentation We report a 9-year-old girl with macrocephaly, gastrointestinal manifestations, hypogammaglobulinemia, and lymphocyte abnormalities. Thyroid function and biochemical screening for SDHB-associated tumors were normal. Trio-based whole-exome sequencing identified a de novo pathogenic PTEN variant, c.464A > G (p.Tyr155Cys), together with a de novo SDHB variant, c.719T > C (p.Leu240Pro). Functional studies showed an increased succinate-to-fumarate ratio and reduced succinate dehydrogenase activity, consistent with impaired mitochondrial complex II function. Structural modeling further suggested that the p.Leu240Pro substitution may reduce SDHB protein stability. Functional evidence fulfilled ACMG/AMP PS3 criteria and supported the proposed reinterpretation of the SDHB variant from a variant of uncertain significance to likely pathogenic using the OddsPath framework. Conclusions This case expands the molecular spectrum of PHTS by describing the coexistence of pathogenic PTEN and functionally supported SDHB variants. Although the phenotype is largely attributable to PHTS, the potential contribution of SDHB dysfunction remains speculative and warrants further investigation. These findings underscore the importance of functional variant interpretation and genotype-informed longitudinal surveillance in rare genetic disorders.
Yaqin Zhang, Sooyeon Lee, Justin P. Annes et al.· Frontiers in Pediatrics· 0 citations
The first prenatal case from a non-consanguineous Chinese family presenting with isolated right pelvicalyceal and ureteral dilation at 24 weeks of gestation is reported, highlighting the utility of prenatal exome sequencing in atypical cases and contributing to the understanding of the expanding genetic and phenotypic landscape of ciliopathies.
Jinyu Liu, Yi Wu, Shixuan Xu et al.· Intractable & Rare Diseases...· 0 citations
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.
Sally Nijim, Mimi Kim, Melissa Denish et al.· Genetics in Medicine· 1 citation
A Chinese patient presenting with classic hallmarks of MGORS7 alongside atypical clinical features, including hearing and visual impairments is reported, suggesting that growth hormone therapy may be beneficial for growth retardation in patients with MGORS7.
Ying Zhao, Yiyang Fu, Shuying Zhang et al.· Frontiers in Genetics· 0 citations