Novel Homozygous Nonsense Mutation Associated with Bardet-Biedl Syndrome in Fetus with Congenital Renal Malformation

Background: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive genetic disorder with clinical and genetic heterogeneity. BBS is more commonly reported in adults and children than in fetuses. Method: Here, a retrospective study of 210 fetuses with congenital renal malformation was performed. These fetuses were performed invasive prenatal diagnosis. Chromosome karyotype analysis, whole exome sequencing (WES), and a single nucleotide polymorphism array (SNP-array) were used.Results: We found the intrauterine phenotype of a fetus with enlarged kidneys, enhanced echo, and oligohydramnios, and the molecular characterizations of the fetus with BBS. The results of chromosome karyotype analysis and SNP-array on the fetus were normal. WES, however, revealed homozygous mutation of c.1177C>T (p.Arg393*) on exon 12 of the BBS1 gene, and heterozygous variation of c.2704G>A (p.Asp902Asn) on exon 22 of the CC2D2A gene. According to ACMG guidelines, c.1177C> T was identified as a pathogenic mutation and c.2704G>A was identified as an uncertain significance. Sanger sequencing showed that there was heterozygous mutation of c.1177C>T and heterozygous variation of c.2704G>A in the parents of the fetus. Conclusion: WES identified a novel homozygous nonsense mutation c.1177C>T in the BBS1 gene of a Chinese fetus with congenital renal malformation. The finding provides more insight into BBS1 mutations in Asian populations in general, and provides a basis for genetic counseling.

Frequency of Confirmed Congenital Renal Malformations in Neonates with Antenatal Diagnosis of Renal Anomalies Presenting In Neonatal Intensive Care Unit of a Tertiary Care Setting of a Low Income Country.

INTRODUCTION:: Approximately 20 to 30% of all anomalies identified in the prenatal period are congenital anomalies of the kidney and urinary tract (CAKUT). Widespread antenatal screening has resulted in increased detection of anomalies of the kidneys and urinary tract. There are limited studies on the postnatal confirmation of these antenatally detected renal malformations. Moreover, there is no local data available in this regard. So, we conducted the study so that we can obtain local data as well as we can plan management and prevention protocols for such chronically, and sometimes critically, ill neonates. MATERIALS AND METHODS:: It was a cross-sectional study conducted at the neonatal intensive care unit (NICU) at the National Institute of Child Health, Karachi during 2017-2018. The sample size was 100 cases. The sampling technique was non-probability consecutive sampling. All neonates aged 1-28 days of either gender admitted in NICU with antenatal diagnosis of congenital renal anomalies on anomaly scan were included in the study. Preterm neonates (gestational age below 34 weeks) and neonates having siblings with similar congenital problems were excluded. RESULTS:: The mean age of the neonates in our study was 10.17 ±9.30 days and the mean gestational age at birth was 36.65 ±1.16 weeks. The majority of the neonates, that is 65%, were males while 35% were females. Sixty-six per cent (66%) neonates were ≤10 days of age while 34% were >10 days of age. Fifty five% of the neonates were ≤36 weeks of gestation at birth while 45% were >36 weeks of gestation at birth. Frequency of postnatally confirmed congenital renal malformation was observed in 78 (78%) neonates. Neonates whose age at presentation was >10 days were slightly more likely to have confirmed congenital renal malformation as compared to neonates with ≤10 days of age, which is 85.3 % vs 74.2 % (p-value 0.206). Males and females were found to have almost equal postnatally confirmed congenital renal malformations (78.5 % in males and 77.1% in females) (p-value 0.879). Postnatally confirmed congenital renal malformations were observed more commonly in neonates who were >36 weeks of gestational age (80%) as compared to those ≤36 weeks of gestational age (76.4%) (p-value 0.662). CONCLUSION::The frequency of confirmed congenital renal malformation was found higher in neonates presenting with antenatal diagnosis of renal anomalies presenting in the neonatal intensive care unit.

Main Physical Features, Echocardiographic and Renal Ultrasonographic Findings of Turner Syndrome in 107 Pediatric Patients

Turner syndrome (TS) is one of the most common malformation syndromes in females. A total number of 107 TS patients, diagnosed between 2000 and 2018, were evaluated for their phenotypic features, and cardiac and renal findings. The mean age of patients at admission was 10.08 ± 4.9 years (range, newborn to 18 years). Four different karyotype groups were encountered, and the most common findings in all groups were short stature, followed by cubitus valgus. Echocardiographic findings of 85 patients were available among which 63 (<i>n</i> = 63/85, 74.1%) were found to be normal. The most common cardiac anomaly was left ventricular outflow tract/aortic arch pathology detected in 9 patients (<i>n</i> = 9/22, 40.9%). Renal malformations were detected in 15 patients (<i>n</i> = 15/84, 17.9%) by renal ultrasonography, and horseshoe kidney was the most common renal malformation, followed by left multicystic dysplastic kidney. There was no significant difference in the frequency of renal malformation and cardiac anomalies among the 4different karyotype groups (χ² exact test, <i>p</i> &#x3e; 0.05). Compared with the literature, the frequency of renal anomalies was detected at a lower rate. Karyotype analysis should be carried out in all female patients with short stature, even if there are no associated phenotypic findings suggestive of TS. Since cardiac anomalies are frequently seen in TS patients and they represent a common cause of mortality, echocardiography should be carried out as soon as the definite diagnosis is established. Renal anomalies may be less frequent than cardiac anomalies; however, evaluation of TS patients with renal ultrasonography should be done at the time of diagnosis. Although renal ultrasonography can be used as the initial renal screening in TS patients, it may underestimate the frequency of renal malformation; hence, further management may be required.

CTU findings of duplex kidney in kidney: A rare duplicated renal malformation

Duplex kidney is a common congenital malformation appeared as duplication of pelvis and ureter. However, renal duplication within sinus renalis is an extremely rare variation of the renal collecting system. In this study, we report a case of an asymptomatic kidney disease in a 33-year-old man, who demonstrates abnormal echo of renal sinus anomaly discovered incidentally in ultrasound examination. Computed tomography urography (CTU) exhibited the other small duplex kidney located in renal sinus. In the excretory phase images, the contrast medium within its small renal pelvis could be seen to flow into the right major renal calices. This case exhibited a very rare anatomical variation of duplicated renal malformation.

Rare heterozygous GDF6 variants in patients with renal anomalies

Although over 50 genes are known to cause renal malformation if mutated, the underlying genetic basis, most easily identified in syndromic cases, remains unsolved in most patients. In search of novel causative genes, whole-exome sequencing in a patient with renal, i.e., crossed fused renal ectopia, and extrarenal, i.e., skeletal, eye, and ear, malformations yielded a rare heterozygous variant in the GDF6 gene encoding growth differentiation factor 6, a member of the BMP family of ligands. Previously, GDF6 variants were reported to cause pleiotropic defects including skeletal, e.g., vertebral, carpal, tarsal fusions, and ocular, e.g., microphthalmia and coloboma, phenotypes. To assess the role of GDF6 in the pathogenesis of renal malformation, we performed targeted sequencing in 193 further patients identifying rare GDF6 variants in two cases with kidney hypodysplasia and extrarenal manifestations. During development, gdf6 was expressed in the pronephric tubule of Xenopus laevis, and Gdf6 expression was observed in the ureteric tree of the murine kidney by RNA in situ hybridization. CRISPR/Cas9-derived knockout of Gdf6 attenuated migration of murine IMCD3 cells, an effect rescued by expression of wild-type but not mutant GDF6, indicating affected variant function regarding a fundamental developmental process. Knockdown of gdf6 in Xenopus laevis resulted in impaired pronephros development. Altogether, we identified rare heterozygous GDF6 variants in 1.6% of all renal anomaly patients and 5.4% of renal anomaly patients additionally manifesting skeletal, ocular, or auricular abnormalities, adding renal hypodysplasia and fusion to the phenotype spectrum of GDF6 variant carriers and suggesting an involvement of GDF6 in nephrogenesis.