Targeted gene sequencing and whole‐exome sequencing in autopsied fetuses with prenatally diagnosed kidney anomalies

Abstract

Identification of fetal kidney anomalies invites questions about underlying causes and recurrence risk in future pregnancies. We therefore investigated the diagnostic yield of next-generation sequencing in fetuses with bilateral kidney anomalies and the correlation between disrupted genes and fetal phenotypes. Fetuses with bilateral kidney anomalies were screened using an in-house-designed kidney-gene panel. In families where candidate variants were not identified, whole-exome sequencing was performed. Genes uncovered by this analysis were added to our kidney panel. We identified likely deleterious variants in 11 of 56 (20%) families. The kidney-gene analysis revealed likely deleterious variants in known kidney developmental genes in 6 fetuses and TMEM67 variants in 2 unrelated fetuses. Kidney histology was similar in the latter 2 fetuses-presenting a distinct prenatal form of nephronophthisis. Exome sequencing identified ROBO1 variants in one family and a GREB1L variant in another family. GREB1L and ROBO1 were added to our kidney-gene panel and additional variants were identified. Next-generation sequencing substantially contributes to identifying causes of fetal kidney anomalies. Genetic causes may be supported by histological examination of the kidneys. This is the first time that SLIT-ROBO signaling is implicated in human bilateral kidney agenesis.

Novel compound heterozygous TMEM67 variants in a Vietnamese family with Joubert syndrome: a case report

“…However, several peculiar phenotypes might be predicted, i.e., TMEM67 missense variants falling in exon 8 to 15, especially combined with a truncating variant would predict to give rise to Meckel-Gruber syndrome. In addition, most of TMEM67 sequence variants were predominantly located in 8 of 28 exons (2,6,8,11,13,15,18,24) [10]. Based on the review of TMEM67 sequence variations previously recorded in the medical literature, our report also showed several mutational hotspots, which were consistent with the result documented by Lannicelli et al, 2010.…”

“…Based on the review of TMEM67 sequence variations previously recorded in the medical literature, our report also showed several mutational hotspots, which were consistent with the result documented by Lannicelli et al, 2010. The most TMEM67 frequently mutated hotspot was exon 8, followed by exons 24,18,6,13,11,2,15 (Table 1).…”

“…Tmem67−/− mutant mice display cerebellar vermis hypoplasia/aplasia, deep interpeduncular fossa and posterior fossa defects compatible with JS phenotype [2]. Biallelic TMEM67 sequence variations cause a wide range of clinical features observed in ciliopathies with multiorgan involvement and different clinical outcomes including JS (MIM 610688), Meckel-Gruber syndrome (MIM 607361), COACH syndrome (Cerebellar vermis hypoplasia, Oligophrenia, Ataxia, Coloboma and Hepatic fibrosis) (MIM 216360), RHYNS syndrome (Retinitis pigmentosa, Hypopituitarism, Nephronophthisis, Skeletal dysplasia), polycystic kidney disease, nephronophthisis-associated ciliopathy (MIM 613550) [3][4][5][6][7] (Table 1). Moreover, TMEM67mutated patients with JS are also at increased risk for liver disease development complicated by probable portal hypertension in the second or third decades of life.…”

Prenatal genetic considerations of congenital anomalies of the kidney and urinary tract (CAKUT)

“…As prenatal WES is being used more commonly in cases with fetal abnormalities and in nonviable pregnancies where microarray is normal, new genes have been identified to explain prenatal renal phenotypes . In this section, we will focus on discussion of recently identified genes that cause congenital abnormalities of the kidney and urinary tract.…”

Investigation of DNA variants specific to ROBO2 Isoform ‘a’ in Irish vesicoureteric reflux patients reveals marked CpG island variation

“…Disruption of a single copy of ROBO2 in a child with a 3;Y translocation through the gene (on Chromosome 3) was found to be the cause of multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects 2 . Screening of patients with non-syndromic VUR has revealed a number of non-synonymous variants in ROBO2 not found in controls [2][3][4][5][6] , though other such variants, predicted to be damaging, have been found in controls 4 , and yet other such variants have been found in other non-syndromic congenital anomalies of the kidneys and urinary tract 6 , and another was found in a fetus with bilateral renal and bladder agenesis and a hypertrophic heart, which also had a non-synonymous SLIT2 variant 7 .…”