Biomedical subjects

Christian Gilissen

Publications and source records attributed to Christian Gilissen.

2 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

Assessing the de novo paradigm in sporadic early-onset Alzheimer disease trios.

The genetic architecture of sporadic Early-Onset Alzheimer Disease (sEOAD, onset ≤65 years) remains largely unknown. To assess the de novo mutation (DNM) hypothesis, we performed a nationwide recruitment of 37 novel sEOAD patients-unaffected parents trios. After assessing known monogenic genes, we performed trio-based exome sequencing and jointly analyzed novel trios with 12 previously reported ones. Of these, we selected 16 trios for genome sequencing. We identified three patients with a pathogenic DNM in APP or PSEN1. Then, from the 46 remaining trios, we identified 38 non-synonymous coding DNM and 4 de novo copy number variants (CNVs) in exome data. Four DNM (2 novel, in SPHK2 and DDR1) and bi-allelic inherited variants in two genes affected Alzheimer disease-related genes. No significant burden of rare coding variants in exome/genome data from 5643 EOAD cases and 16097 controls was identified using nested windows centered on each DNM position, at the transcript level. From genome data, one non-coding DNM was predicted to affect splicing in an AD-associated gene, PINX1. Overall, 48% probands carried ≥1 inherited risk factor with odds ratio (OR) > 1.5 and GWAS-defined Genetic Risk Scores (GRS) distribution was more consistent with random distribution than enrichment in higher scores in probands. We confirm that DNMs in known monogenic genes explain sEOAD in a minority of cases, while candidate DNMs in other genes might account for a small proportion of additional cases. The majority of sEOAD patients may have a complex etiology including multiple inherited variants, however, GRS might not explain most of its genetic component.

Humans↗