Biomedical subjects

Kun Xia

Publications and source records attributed to Kun Xia.

3 recordsLinked to original sources

PubMed2026

Characterization of the genotypic and phenotypic spectrum of TCF7L2-related neurodevelopmental disorder (TRND).

PURPOSE: TCF7L2 (OMIM 602228; HGNC:11641) is a transcription factor and a critical effector of the Wnt/ β-Catenin pathway. In 2021, 11 pediatric patients with monoallelic 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-is urgently needed. METHODS: We leveraged multiple methods (eg, GeneMatcher, DECIPHER, literature review, and 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 more than 60,000 PennMedicine BioBank 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 the most commonly observed. Phenotypic differences did not cluster by variant type or genomic locus. Among PennMedicine BioBank patients, an association of nominal significance with type 2 diabetes with renal manifestations (odds ratio = 5.8; P = .03) was detected, warranting further investigation. CONCLUSION: This study represents the most comprehensive characterization of TCF7L2-related neurodevelopmental disorder to date, a novel neurodevelopmental disorder, defining its genotypic and phenotypic spectra. We opened a Simons Searchlight natural history study that is now available for patient enrollment to enhance the understanding of this condition.

Neurodevelopmental syndrome↗

PubMed2026

CHST5 gene mutations contribute to high myopia by disrupting collagen fiber organization.

High myopia (HM) is a leading cause of irreversible vision loss in working-age adults. Its pathogenesis is characterized by alterations in the microstructure and composition of collagen fibers, and genetic factors make a substantial contribution. In this study, we identify carbohydrate sulfotransferase 5 (CHST5) as a candidate gene for HM in humans and mice, with its mutations disrupting collagen fiber organization. The c.444C>A (p.S148R) variant in CHST5, a gene critical for sulfating corneal keratan sulfate (KS), completely co-segregates with HM in a Chinese family. Screening of CHST5 variants in 320 HM patients identifies two additional ones. We further find that Chst5 is expressed primarily in the cornea and sclera of mouse ocular tissues, and that the mutant protein CHST5S148R loses its Golgi localization. Homozygous mutant Chst5S126R mice exhibit HM phenotypes, including myopic refractive error (RE), significantly thinner sclera and cornea, notable microstructural changes in scleral and corneal collagen fibers, and shorter corneal KS chains. Our findings suggest that CHST5 NM_024533.5 c.444C>A (p.S148R) causes loss of proper protein localization, likely impairing its sulfotransferase function. This defect disrupts the organization of corneal and scleral collagen fibers and ultimately contributes to the development and progression of HM.

CHST5↗

PubMed2026

Evidence supporting the role of GIGYF2 in synapse development and autism.

Autism spectrum disorder (ASD) is a heterogeneous condition in which genetically defined subtypes offered insights into underlying biological mechanisms and potential targeted treatments. Here, we investigate the clinical and pathogenic significance of GIGYF2 variants in ASD through an integrated approach combining clinical genetics, conditional knockout (cKO) mouse models, neurobiology, and molecular studies. Through targeted sequencing, large-scale genomic data analysis of neurodevelopmental disorder cohorts, and international collaborations, we identified ten affected individuals from eight families harboring de novo or dominantly inherited likely gene-disruptive (LGD) variants and 13 affected individuals from 13 families with de novo missense variants in GIGYF2. Clinical characterization of 16 probands with GIGYF2 variants revealed common features, including ASD, language problems, intellectual disability, and anxiety. In a Gigyf2 cKO mouse model, we observed pronounced autistic-like behaviors, cognitive deficits, and anxiety-like behaviors, mirroring phenotypes observed in affected individuals. Mechanistically, Gigyf2 deficiency disrupted synaptic homeostasis, as evidenced by altered spine density and miniature excitatory postsynaptic currents, and impaired IGF-1R/mTOR signaling, along with dysregulation of synapse-related genes such as Nrp2. Pharmacological inhibition of mTOR with rapamycin or Torin1, as well as Nrp2 knockdown rescued synaptic defects in Gigyf2 KO neurons. These findings define a novel ASD subtype associated with GIGYF2 variants and establish GIGYF2 as a key regulator of synaptic development and function, implicating GIGYF2 dysfunction in ASD pathogenesis and highlighting the IGF-1R/mTOR pathway as a potential therapeutic target for GIGYF2-related ASD subtype.

Journal Article↗