Predicting and quantifying phenotypic consequences of genetic variants in rare disorders is a major challenge, particularly pertinent for 'actionable' genes such as thyroid hormone transporter MCT8 (encoded by the X-linked SLC16A2 gene), where loss-of-function (LoF) variants cause a rare neurodevelopmental and (treatable) metabolic disorder in males. The combination of deep phenotyping data with functional and computational tests and with outcomes in population cohorts, enabled us to: (i) identify the genetic aetiology of divergent clinical phenotypes of MCT8 deficiency with genotype-phenotype relationships present across survival and 24 out of 32 disease features; (ii) demonstrate a mild phenocopy in ~400,000 individuals with common genetic variants in MCT8; (iii) assess therapeutic effectiveness, which did not differ among LoF-categories; (iv) advance structural insights in normal and mutated MCT8 by delineating seven critical functional domains; (v) create a pathogenicity-severity MCT8 variant classifier that accurately predicted pathogenicity (AUC:0.91) and severity (AUC:0.
View Article and Find Full Text PDFObjective: To investigate the current genetic counseling practices involving a cfDNA result indicating mosaic monosomy X of likely maternal origin, and to better understand the perspectives of patients who have received this result.
Method: A total of 60 prenatal genetic counselors completed surveys about their experiences with this result, cfDNA consenting practices, and management practices. In addition, qualitative interviews were conducted with 5 patients to gain insight into their experiences with result disclosure and follow-up care.
Loeys-Dietz syndrome (LDS) is a connective tissue disorder representing a wide spectrum of phenotypes, ranging from isolated thoracic aortic aneurysm or dissection to a more severe syndromic presentation with multisystemic involvement. Significant clinical variability has been noted for both related and unrelated individuals with the same pathogenic variant. We report a family of five affected individuals with notable phenotypic variability who appear to have two distinct molecular causes of LDS, one attributable to a missense variant in and the other an intronic variant 6 bp upstream from a splice junction in .
View Article and Find Full Text PDFAplastic anemia, characterized by pancytopenia and hypoplastic bone marrow, is associated with various acquired cytogenetic abnormalities, including trisomy 8, in 4%-15% of patients. Constitutional mosaic trisomy 8 notably increases the risks for cytopenia and myeloid malignancies. Duplications near chromosome 8 centromere are associated with developmental delays, autism, and trisomy 8p11.
View Article and Find Full Text PDFAm J Med Genet C Semin Med Genet
November 2024
Neurons form the basic anatomical and functional structure of the nervous system, and defects in neuronal differentiation or formation of neurites are associated with various psychiatric and neurodevelopmental disorders. Dynamic changes in the cytoskeleton are essential for this process, which is, inter alia, controlled by the dedicator of cytokinesis 4 (DOCK4) through the activation of RAC1. Here, we clinically describe 7 individuals (6 males and one female) with variants in DOCK4 and overlapping phenotype of mild to severe global developmental delay.
View Article and Find Full Text PDFFront Public Health
January 2024
Background: Screening for germline pathogenic or variants (gBRCA) in high-risk breast cancer patients is known to be cost-effective in high-income countries. Nationwide adoption of genetics testing in high-risk breast cancer population remains poor. Our study aimed to assess gBRCA health economics data in the middle-income country setting of Thailand.
View Article and Find Full Text PDFObjective: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4-related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail.
View Article and Find Full Text PDFAm J Med Genet C Semin Med Genet
November 2024
Purpose: Multiple studies suggest an association between DLG2 and neurodevelopmental disorders and indicate the haploinsufficiency of this gene; however, few cases have been thoroughly described. We performed additional studies to confirm this clinical association and DLG2 haploinsufficiency.
Methods: Chromosomal microarray analysis was performed on 11,107 patients at the Cytogenetics Laboratory at the University of Alabama at Birmingham.
GM3 synthase deficiency (GM3SD) is caused by biallelic variants in . The ganglioside GM3, enriched in neuronal tissues, is a component of lipid rafts and regulates numerous signaling pathways. Affected individuals with GM3SD exhibit global developmental delay, progressive microcephaly, and dyskinetic movements.
View Article and Find Full Text PDFHorm Res Paediatr
August 2023
Introduction: There are two major categories of peroxisomal disorders (PDs): peroxisomal biogenesis disorders (PBDs) due to defects in peroxisomal (PEX) genes and deficiency of other peroxisomal enzymes (such as D-bifunctional enzyme deficiency due to HSD17B4). PDs are characterized by abnormal elevations of very-long-chain fatty acids (VLCFA). We aimed to evaluate the clinical phenotype of adrenal insufficiency in patients with PD and to assess any genotype-phenotype correlations with adrenal insufficiency.
View Article and Find Full Text PDFNeurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants.
View Article and Find Full Text PDF