Postnatal Outcomes of Fetuses with Prenatal Diagnosis of 6-9.9 mm Pyelectasis.

Pyelectasis, also known as renal pelvic dilatation or hydronephrosis, is frequently found on fetal ultrasound. This study correlated prenatally-detected, moderate pyelectasis with postnatal outcomes. This retrospective, observational study was conducted at a tertiary medical center in Israel. The study group consisted of 54 fetuses with prenatal diagnosis of pyelectasis on ultrasound scan during the second trimester, defined as anteroposterior renal pelvic diameter (APRPD) 6-9.9 mm. Long-term postnatal outcomes and renal-related sequelae were obtained using medical records and telephone-based questionnaires. The control group included 98 cases with APRPD < 6 mm. Results indicate that fetal pyelectasis 6-9.9 mm was more frequent among males (68.5%) than females (51%, p = 0.034). We did not find significant correlations between 6-9.9 mm pyelectasis and other anomalies or chromosomal/genetic disorders. Pyelectasis resolved during the pregnancy in 15/54 (27.8%) cases. There was no change in 17/54 (31.5%) and 22/54 (40.7%) progressed to hydronephrosis Among the study group, 25/54 (46.3%) were diagnosed with neonatal hydronephrosis. There were more cases of renal reflux or renal obstruction in the study group compared to the control group 8/54 (14.8%) vs. 1/98 (1.0%), respectively; p = 0.002. In conclusion, most cases of 6-9.9 mm pyelectasis remained stable or resolved spontaneously during pregnancy. There was a higher rate of postnatal renal reflux and renal obstruction in this group; however, most did not require surgical intervention.

A unique PRDM13-associated variant in a Georgian Jewish family with probable North Carolina macular dystrophy and the possible contribution of a unique CFH variant.

Purpose: North Carolina macular dystrophy (NCMD) is an autosomal dominant maculopathy that is considered a non-progressive developmental disorder with variable expressivity. Our study aimed to clinically and genetically characterize macular dystrophy in a family (MOL1154) consisting of six affected subjects with a highly variable maculopathy phenotype in which no correlation between age and severity exists. Methods: Clinical characterization included visual acuity testing and electroretinography. Genetic analysis included Sanger sequencing and whole exome sequencing (WES). Results: WES analysis performed on DNA samples from two individuals revealed a heterozygous deletion of six nucleotides [c.2247_2252del; p.(Leu750_Lys751del)] in the CFH gene. Co-segregation analysis revealed that five of the six NCMD affected subjects carried this deletion, while one individual who had a relatively mild phenotype compatible with dry age-related macular degeneration (AMD) did not carry it. We subsequently analyzed the upstream region of PRDM13 that has previously been reported to be associated with NCMD and identified a unique heterozygous transversion (chr6:100040974A>C) located within the previously described suspected control region in all six affected individuals. This transversion is likely to cause NCMD. Conclusions: NCMD has a wide spectrum of clinical phenotypes that can overlap with AMD, making it challenging to correctly diagnose affected individuals and family members. The DNA sequence variant we found in the CFH gene of some of the affected family members may suggest some role as a modifier gene. However, this variant still does not explain the huge phenotypic variability of NCMD and needs to be studied in other and larger populations.

Identification of genomic deletions causing inherited retinal degenerations by coverage analysis of whole exome sequencing data.

BACKGROUND: Inherited retinal degenerations (IRDs) are a common cause of visual disturbance with a high clinical and genetic heterogeneity. Recent sequencing techniques such as whole exome sequencing (WES) contribute to the discovery of novel genes. The aim of the current study was to use WES data to identify large deletions that include at least one exon in known IRD genes. METHODS: Patients diagnosed with IRDs underwent a comprehensive ophthalmic evaluation. WES was performed using the NimbleGen V2 paired-end kit and HiSeq 2000. An analysis of exon coverage data was performed on 60 WES samples. Exonic deletions were verified by 'PCR walking' analysis. RESULTS: We analysed data obtained from 60 WES samples of index patients with IRDs. By calculating the average coverage for all exons in the human genome, we were able to identify homozygous and hemizygous deletions of at least one exon in six families (10%), including a single-exon deletion in EYS, deletions of three consecutive exons in MYO7A and NPHP4, deletions of four and eight consecutive exons in RPGR and a multigene deletion on the X-chromosome, including CHM. By using PCR-walking analysis, we were able to identify the borders of five of the deletions and to screen our set of patients for these deletions. CONCLUSIONS: We performed here a comprehensive analysis of WES data as a tool for identifying large genomic deletions in patients with IRDs. Our analysis indicates that large deletions are relatively frequent (about 10% of our WES cohort) and should be screened when analysing WES data.

Genetic Analysis of the Rhodopsin Gene Identifies a Mosaic Dominant Retinitis Pigmentosa Mutation in a Healthy Individual.

PURPOSE: Retinitis pigmentosa (RP) is a group of clinically and genetically heterogeneous hereditary retinal diseases that result in blindness due to photoreceptor degeneration. Mutations in the rhodopsin (RHO) gene are the most common cause of autosomal dominant RP (adRP) and are responsible for 16% to 35% of adRP cases in the Western population. Our purpose was to investigate the contribution of RHO to adRP in the Israeli and Palestinian populations. METHODS: Thirty-two adRP families participated in the study. Mutation detection was performed by whole exome sequencing (WES) and Sanger sequencing of RHO exons. Fluorescence PCR reactions of serially diluted samples were used to predict the percentage of mosaic cells in blood samples. RESULTS: Eight RHO disease-causing mutations were identified in nine families, with only one novel mutation, c.548-638dup91bp, identified in a family where WES failed to detect any causal variant. Segregation analysis revealed that the origin of the mutation is in a mosaic healthy individual carrying the mutation in approximately 13% of blood cells. CONCLUSIONS: This is the first report of the mutation spectrum of a known adRP gene in the Israeli and Palestinian populations, leading to the identification of seven previously reported mutations and one novel mutation. Our study shows that RHO mutations are a major cause of adRP in this cohort and are responsible for 28% of adRP families. The novel mutation exhibits a unique phenomenon in which an unaffected individual is mosaic for an adRP-causing mutation.