👤 Mikhail Skoblov

Developmental and epileptic encephalopathies (DEEs) comprise a diverse range of disorders that can arise from both genetic and non-genetic causes. Genetic DEEs are linked to pathogenic variants in various genes with different molecular functions. The wide clinical and genetic variability found in DEEs poses a considerable challenge for accurate diagnosis even with the use of comprehensive diagnostic approaches such as whole genome sequencing (WGS). In this study, we describe a girl with a clinical presentation of DEE. Using WGS, we identified several candidate variants in the HNRNPU, NIPBL, and KANSL1 genes with partial overlap with the patient's clinical presentation. Subsequent analysis revealed that only the variant in the HNRNPU gene arose de novo, while the others were inherited from unaffected parents. The variant in HNRNPU was determined to be causative. However, the previously reported pathogenic loss-of-function (LoF) variant in KANSL1, inherited from a healthy mother, complicated the interpretation of the results. A thorough investigation using RNA analysis showed that the variant in the KANSL1 gene is located in a duplicated locus, which does not produce a functional protein, explaining the lack of the variant's contribution to the development of the pathological phenotype. This case illustrates the importance of integrating WGS with additional analyses to accurately diagnose and understand the molecular basis of the lack of influence of the LoF variant in KANSL1 on the patient's phenotype. Show less

Multiple osteochondromas (MO) is a rare autosomal dominant skeletal disorder characterized by the development of multiple benign tumors known as osteochondromas. The condition is predominantly caused by loss-of-function variants in the Show less

This study is aimed at investigating the clinical and genetic characteristics of 244 unrelated probands diagnosed with multiple osteochondromas (MO). The diagnosis of MO typically involves identifying multiple benign bone tumors known as osteochondromas (OCs) through imaging studies and physical examinations. However, cases with both OCs and enchondromas (ECs) may indicate the more rare condition metachondromatosis (MC), which is assumed to be distinct disease. Previous cohort studies of MO found heterozygous loss-of-function (LoF) variants only in the Show less