LRP1 encodes the low-density lipoprotein (LDL) receptor-related protein 1 (LRP1), a transmembrane protein involved in endocytosis and activation of multiple signaling pathways. LRP1 variants have been implicated in the pathogenesis of congenital heart defects (CHD), Alzheimer's disease, and neurodevelopmental disorders (NDD). Biallelic LRP1 variants have also been reported in two siblings with CHD, hypotonia, dysmorphology, corneal clouding, and ascites. However, conclusive evidence supporting the role of LRP1 in human disease is still lacking. Individuals with heterozygous variants in LRP1 (NM_002332.3) were identified through genetic testing. GeneMatcher facilitated identification of participants and international collaboration. Comprehensive clinical and genotypic data were collected. Fifteen participants with heterozygous predicted loss-of-function (pLOF) or missense variants in LRP1 were identified. The most common phenotypes include NDD, CHD, musculoskeletal and gastrointestinal issues, and dysmorphic features. CHD was more common in participants with pLOF variants. Our findings suggest that LRP1 haploinsufficiency is associated with a syndromic NDD. Phenotypic differences in cardiac and neurologic involvement between participants with pLOF and missense variants suggest the possibility of alternate disease mechanisms.
Alyssa L. Rippert, G. Arnadottir, Laura Bedinger et al.· American Journal of Medical...· 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
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