Clinical Genetics最新文献

Autosomal recessive polycystic kidney disease (ARPKD) is a rare but severe hereditary renal disorder characterized by bilaterally enlarged, cystic kidneys and varying degrees of hepatic fibrosis, often leading to early-onset kidney failure and significant morbidity. While most ARPKD cases are linked to mutations in the PKHD1 gene, recent advances in genomic sequencing have revealed that mutations in other genes, including PDIA6, may contribute to similar phenotypes. The PDIA6 gene encodes protein disulfide isomerase A6, which plays a critical role in protein folding within the endoplasmic reticulum (ER) and in the regulation of ER stress responses. Here, we report a rare and complex case of a full-term male neonate born to consanguineous Syrian refugee parents, who presented with a clinical constellation of features including polycystic kidney disease, severe oligohydramnios, pulmonary hypoplasia, microcephaly, rib thoracic dysplasia, and global developmental delay. Genetic analysis using whole-exome sequencing identified a homozygous two-base deletion in exon 5 of the PDIA6, resulting in a premature stop codon. Early diagnosis via genomic tools is essential for prognosis, management, and genetic counseling.

The study aimed to report genotype–phenotype correlation in children with cystic fibrosis. This prospective multicentric study was done at four centres. Variants were tested for two common variants, followed by exome sequencing using NGS. Patients with cystic fibrosis who have one or more pathogenic/likely pathogenic variants were included in this study. The study included 260 children. Boys were more common (70.6% vs. 55.3%), and consanguinity was more prevalent (31.7% vs. 14.2%) in patients with non-c.1520_1522del variants. The 3849+10kbC>T variant had less pancreatic insufficiency, a higher age at diagnosis, and lower sweat chloride values compared to the c.1520_1522del variant. The median (IQR) age at diagnosis was significantly lower [1.5 (0.5, 7) vs. 4 (1.1, 9.4 years)], and pancreatic insufficiency (80.4% vs. 66.4%) and consanguinity (44% vs. 7.1%) were significantly more frequent in patients with homozygous variants compared to compound heterozygous variants. There was no difference in the proportion of Pseudomonas or Staphylococcus colonisation, spirometry parameters or frequency of bronchiectasis amongst various genetic groups. To conclude, the proportion of boys and consanguinity was higher with non-c.1520_1522del variants. The 3849+10kbC>T variant exhibited some peculiar phenotypic features. The patients with homozygous variants were younger at diagnosis and had higher pancreatic insufficiency.

Studies from the subcontinent on the utility of Whole Exome Sequencing (WES) in electro-clinical phenotypes of childhood-onset drug-resistant epilepsy (DRE) syndromes, particularly the developmental and epileptic encephalopathies (DEE), are rare in the literature. Patients with DRE phenotypes of presumed genetic etiology with an age of onset of epilepsy < 12 years, with/without developmental encephalopathy, were included in this study. Our study cohort (N = 175) included 158 trios, 6 duos, and 11 proband-only samples. Age at onset of seizures was ≤ 3 years in 76.6% and > 3 years in 23.4%, with developmental delay noted in 80.6% of the cohort. The overall yield of pathogenic/likely pathogenic variants in WES was 38.9% (68/175, 19 were novel); for trio-WES it was 41.1%. Predominantly de novo variants accounted for 45 out of 68 cases (66.2%), and the most frequent disease-causing variants were missense (74%). Younger age at onset of epilepsy, female gender and electroclinical diagnosis of Dravet syndrome were associated with a higher yield as opposed to focal epilepsies. Precision medicine was considered tenable in 25/68 (36.8%) cases. Our study reveals a significant yield of trio-WES for de novo variants in childhood-onset DRE/DEE. Female gender, early age at onset, and specific electro-clinical phenotypes have a higher likelihood of identifying a monogenic etiology.

Mediator of DNA damage checkpoint 1 (MDC1) is a protein closely associated with the repair of DNA damage. Recently, we identified three novel variants (NM_014641.3:c.C5977T; p.R1993X) (NM_014641.3:c.C5644T; p.R1882X; c.A1T; p.M1L) in MDC1 in two patients with severe oligoasthenoteratozoospermia (OAT). In vitro validation showed that the p.R1882X variant resulted in the truncation of the MDC1 protein, and the p.R1993X variant resulted in the degradation of the MDC1 protein after truncation. Immunofluorescence demonstrated that the truncated protein caused by the variants affected the colocalization relationship between MDC1 and its interacting protein γH2AX. Additionally, one of the patients and his wife underwent intracytoplasmic sperm injection (ICSI), but the result was unsatisfactory. We screened out the variants of MDC1 in patients with OAT for the first time, and this research could afford precise genetic diagnosis for the patients. It has broadened the variant spectrum of MDC1 , which is conducive to the development of targeted therapeutic strategies.

Genetic skeletal disorders (GSDs) comprise a diverse group of disorders that affect bone development and homeostasis. In some areas of Iran, GSD occurs more frequently than in other places for still unknown reasons. The aim of this study was to characterize the genetic landscape of GSDs in a cohort from southwestern Iran using Exome sequencing (ES), with a focus on identifying pathogenic and likely pathogenic variants. Osteogenesis Imperfecta (OI) was the most prevalent disorder, with an unexpectedly high frequency of autosomal recessive subtypes, likely due to a high consanguinity rate (61.3%) in the cohort. Achondroplasia (ACH) was the second most common disease and, comparable to another population, the NM_000142.5:c.1138G>A, p.(Gly380Arg), was the most common variant in FGFR3. ES identified twenty novel and fifteen previously reported pathogenic variants in several genes associated with GSDs. We provide the first comprehensive ES-based molecular diagnosis of GSDs in an Iranian population and uncover novel pathogenic variants that expand the known spectrum of variants. The results underscore the importance of genetic testing in the diagnosis of rare skeletal diseases and highlight the need for targeted genetic counseling in populations with high consanguinity.

LONP1 encodes a mitochondrial protease essential for protein quality control and metabolism. Variants in LONP1 are associated with a diverse and expanding spectrum of disorders, including Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies syndrome (CODAS), congenital diaphragmatic hernia (CDH), and neurodevelopmental disorders (NDD), with some individuals exhibiting features of mitochondrial encephalopathy. We report 16 novel LONP1 variants identified in 16 individuals (11 with NDD, 5 with CDH), further expanding the clinical spectrum. Structural mapping of disease-associated missense variants revealed phenotype-specific clustering, with CODAS variants enriched in the proteolytic chamber and NDD variants more broadly distributed. CODAS is caused by biallelic variants and CDH by monoallelic variants, both of which are predicted to act through loss-of-function mechanisms. Both monoallelic and biallelic variants are associated with LONP1-related NDD, suggesting complex mechanisms such as dominant-negative effects. Our findings broaden the phenotypic and genetic spectrum of LONP1-associated disorders and highlight the essential role of LONP1 in mitochondrial function and development.