Kidney Disease Associated With Mono-allelic and Variants: A Case Series of 17 Families.

Rationale & Objective: Mono-allelic variants in and () have been identified in a spectrum of glomerular basement membrane nephropathies, including thin basement membrane nephropathy and autosomal dominant Alport syndrome. With the increasing use of next generation sequencing, mono-allelic variants are detected more frequently, but phenotypic heterogeneity impedes counseling. We aimed to investigate the phenotypic spectrum, kidney biopsy results, and segregation patterns of patients with mono-allelic / variants identified by whole exome sequencing.

Combined germline pathogenic variants in FLCN and TP53 are associated with early onset renal cell carcinoma and brain tumors.

Background: We present a family consisting of a father and his two children with an exceptional phenotype of childhood renal cell carcinoma and brain tumors. Extensive genetic testing revealed two inherited tumor predisposition syndromes in all three family members: Birt-Hogg-Dubé syndrome and Li-Fraumeni syndrome. The corresponding genes (FLCN and TP53) are both located on the short arm of chromosome 17.

The phenotypic spectrum and genotype-phenotype correlations in 106 patients with variants in major autism gene CHD8.

CHD8, a major autism gene, functions in chromatin remodelling and has various roles involving several biological pathways. Therefore, unsurprisingly, previous studies have shown that intellectual developmental disorder with autism and macrocephaly (IDDAM), the syndrome caused by pathogenic variants in CHD8, consists of a broad range of phenotypic abnormalities. We collected and reviewed 106 individuals with IDDAM, including 36 individuals not previously published, thus enabling thorough genotype-phenotype analyses, involving the CHD8 mutation spectrum, characterization of the CHD8 DNA methylation episignature, and the systematic analysis of phenotypes collected in Human Phenotype Ontology (HPO).

Identical Variants Cause Variable Skeletal Ciliopathy Phenotypes-Challenges for the Accurate Diagnosis.

Ciliopathies are rare congenital disorders, caused by defects in the cilium, that cover a broad clinical spectrum. A subgroup of ciliopathies showing significant phenotypic overlap are known as skeletal ciliopathies and include Jeune asphyxiating thoracic dysplasia (JATD), Mainzer-Saldino syndrome (MZSDS), cranioectodermal dysplasia (CED), and short-rib polydactyly (SRP). Ciliopathies are heterogeneous disorders with >187 associated genes, of which some genes are described to cause more than one ciliopathy phenotype.

Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA.

Background: Gitelman syndrome is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. Gitelman syndrome is caused by biallelic pathogenic variants in encoding the Na-Cl cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of , , , or may result in the same renal phenotype of Gitelman syndrome, as they can lead to reduced NCC activity.