The First Pediatric Case of an IFT140 Heterozygous Deletion Causing Autosomal Dominant Polycystic Kidney Disease: Case Report.

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease, which is mainly caused by pathogenic variants in two particular genes: PKD1 and PKD2. ADPKD caused by variants in other genes (GANAB or IFT140) is very rare. Case Report: In a 6-year-old girl examined for abdominal pain, a cystic mass in the upper part of the right kidney was detected during an abdominal ultrasound. She was referred to pediatric oncology and urology for suspicion of a tumorous mass and the condition was assessed as a cystic nephroma. A heminephrectomy was then performed on the upper cystic part of the right kidney. The histological examination was inconclusive; therefore, genetic testing was recommended. Kidney and liver cysts were detected sonographically in the mother, but DNA analysis of the PKD1 and PKD2 genes did not reveal any pathogenic variant; the cause of the pathological formation in the kidneys remained unclear. Nine years later, next-generation sequencing of a panel of genes for kidney disease was performed and a heterozygous deletion was found on chromosome 16; this included exon 13 of the IFT140 gene. The same deletion was found in the patient's mother. Currently, the patient is 14 years old and has mild sonographic findings, normal glomerular filtration, mild proteinuria, and hypertension. Conclusion: Pathogenic variants of the IFT140 gene very rarely cause ADPKD; however, they should be considered in all children with autosomal dominant forms of PKD and asymmetric/atypical cystic kidney involvement or negative findings of PKD1 and PKD2.

A founder COL4A4 pathogenic variant resulting in autosomal recessive Alport syndrome accounts for most genetic kidney failure in Romani people.

Introduction: Romani people have a high prevalence of kidney failure. This study examined a Romani cohort for pathogenic variants in the COL4A3, COL4A4, and COL4A5 genes that are affected in Alport syndrome (AS), a common cause of genetic kidney disease, characterized by hematuria, proteinuria, end-stage kidney failure, hearing loss, and eye anomalies. Materials and methods: The study included 57 Romani from different families with clinical features that suggested AS who underwent next-generation sequencing (NGS) of the COL4A3, COL4A4, and COL4A5 genes, and 83 family members. Results: In total, 27 Romani (19%) had autosomal recessive AS caused by a homozygous pathogenic c.1598G>A, p.Gly533Asp variant in COL4A4 (n = 20) or a homozygous c.415G>C, p.Gly139Arg variant in COL4A3 (n = 7). For p.Gly533Asp, 12 (80%) had macroscopic hematuria, 12 (63%) developed end-stage kidney failure at a median age of 22 years, and 13 (67%) had hearing loss. For p.Gly139Arg, none had macroscopic hematuria (p = 0.023), three (50%) had end-stage kidney failure by a median age of 42 years (p = 0.653), and five (83%) had hearing loss (p = 0.367). The p.Gly533Asp variant was associated with a more severe phenotype than p.Gly139Arg, with an earlier age at end-stage kidney failure and more macroscopic hematuria. Microscopic hematuria was very common in heterozygotes with both p.Gly533Asp (91%) and p.Gly139Arg (92%). Conclusion: These two founder variants contribute to the high prevalence of kidney failure in Czech Romani. The estimated population frequency of autosomal recessive AS from these variants and consanguinity by descent is at least 1:11,000 in Czech Romani. This corresponds to a population frequency of autosomal dominant AS from these two variants alone of 1%. Romani with persistent hematuria should be offered genetic testing.

Multigene Panel Germline Testing of 1333 Czech Patients with Ovarian Cancer.

Ovarian cancer (OC) is the deadliest gynecologic malignancy with a substantial proportion of hereditary cases and a frequent association with breast cancer (BC). Genetic testing facilitates treatment and preventive strategies reducing OC mortality in mutation carriers. However, the prevalence of germline mutations varies among populations and many rarely mutated OC predisposition genes remain to be identified. We aimed to analyze 219 genes in 1333 Czech OC patients and 2278 population-matched controls using next-generation sequencing. We revealed germline mutations in 18 OC/BC predisposition genes in 32.0% of patients and in 2.5% of controls. Mutations in BRCA1/BRCA2, RAD51C/RAD51D, BARD1, and mismatch repair genes conferred high OC risk (OR > 5). Mutations in BRIP1 and NBN were associated with moderate risk (both OR = 3.5). BRCA1/2 mutations dominated in almost all clinicopathological subgroups including sporadic borderline tumors of ovary (BTO). Analysis of remaining 201 genes revealed somatic mosaics in PPM1D and germline mutations in SHPRH and NAT1 associating with a high/moderate OC risk significantly; however, further studies are warranted to delineate their contribution to OC development in other populations. Our findings demonstrate the high proportion of patients with hereditary OC in Slavic population justifying genetic testing in all patients with OC, including BTO.