Targeted next‐generation sequencing in a large series of fetuses with severe renal diseases

• Published in: Human mutation Vol. 43; no. 3; pp. 347 - 361
• Main Authors: Jordan, Penelope, Dorval, Guillaume, Arrondel, Christelle, Morinière, Vincent, Tournant, Carole, Audrezet, Marie‐Pierre, Michel‐Calemard, Laurence, Putoux, Audrey, Lesca, Gaethan, Labalme, Audrey, Whalen, Sandra, Loeuillet, Laurence, Martinovic, Jelena, Attie‐Bitach, Tania, Bessières, Bettina, Schaefer, Elise, Scheidecker, Sophie, Lambert, Laetitia, Beneteau, Claire, Patat, Olivier, Boute‐Benejean, Odile, Molin, Arnaud, Guimiot, Fabien, Fontanarosa, Nicolas, Nizon, Mathilde, Lefebvre, Mathilde, Jeanpierre, Cécile, Saunier, Sophie, Heidet, Laurence
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.03.2022; Wiley
• Subjects: Antigens, Neoplasm; Cell Cycle Proteins - genetics; congenital abnormalities of the kidney and urinary tract; Congenital defects; Cytoskeletal Proteins - genetics; DNA sequencing; Female; fetal renal diseases; Fetus - abnormalities; Fetuses; Genetic counseling; Genotype & phenotype; Heredity; High-Throughput Nucleotide Sequencing; Homozygote; Humans; Kidney - abnormalities; Kidney diseases; Kidney Diseases - congenital; Kidney Diseases - diagnosis; Kidney Diseases - genetics; Life Sciences; Male; Mutation; NGS targeted RNA sequencing; Pax2 protein; Phenotypes; Polycystic kidney; Polycystic Kidney, Autosomal Dominant - genetics; renal ciliopathies; renal tubular dysgenesis; Urinary tract; renal ciliopathies; congenital abnormalities of the kidney and urinary tract; fetal renal diseases; renal tubular dysgenesis; NGS targeted RNA sequencing
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.24324

We report the screening of a large panel of genes in a series of 100 fetuses (98 families) affected with severe renal defects. Causative variants were identified in 22% of cases, greatly improving genetic counseling. The percentage of variants explaining the phenotype was different according to the type of phenotype. The highest diagnostic yield was found in cases affected with the ciliopathy‐like phenotype (11/15 families and, in addition, a single heterozygous or a homozygous Class 3 variant in PKHD1 in three unrelated cases with autosomal recessive polycystic kidney disease). The lowest diagnostic yield was observed in cases with congenital anomalies of the kidney and urinary tract (9/78 families and, in addition, Class 3 variants in GREB1L in three unrelated cases with bilateral renal agenesis). Inheritance was autosomal recessive in nine genes (PKHD1, NPHP3, CEP290, TMEM67, DNAJB11, FRAS1, ACE, AGT, and AGTR1), and autosomal dominant in six genes (PKD1, PKD2, PAX2, EYA1, BICC1, and MYOCD). Finally, we developed an original approach of next‐generation sequencing targeted RNA sequencing using the custom capture panel used for the sequencing of DNA, to validate one MYOCD heterozygous splicing variant identified in two male siblings with megabladder and inherited from their healthy mother.