Search

Autosomal recessive conditions are common in consanguineous populations. Since consanguinity is common in the Israeli Arab population, we evaluated the rate of MUTYH polyposis (MAP) among polyposis patients in this population and studied Pathogenic Variants (PVs) spectrum. We reviewed health records of all Arab and Druze polyposis patients referred for counseling during 2013–2020 who fulfilled the Israeli Genetic Society criteria for MUTYH/APC testing, in a tertiary center in Northern Israel and four additional gastro-genetic clinics in Israel. The Northern cohort included 37 patients from 30 unrelated families; 8(26.6%) carried bi-allelic MUTYH PVs. The major variant p.Glu452del was detected in 6/8 Druze and Muslim families who shared the same haplotype. Other PVs detected in both cohorts included p.Tyr56Ter, p.His57Arg, c.849+3A>C, p.Ala357fs, and p.Tyr151Cys. Among bi-allelic carriers, 88% reported consanguinity, and 100% had positive family history for polyposis or colorectal cancer (CRC). Generally, the age of CRC was 10 years younger than reported in the general MAP population. MAP accounted for 27% of polyposis cases in the Arab population of Northern Israel. PVs spectrum is unique, with high frequency of the founder variant p.Glu452del. Our results may inform the genetic testing strategy in the Israeli Arab population. [ABSTRACT FROM AUTHOR]

Leukodystrophies are monogenic disorders primarily affecting the white matter. We aimed to evaluate the utility of genetic testing and time-to-diagnosis in a retrospective cohort of children with suspected leukodystrophy. Medical records of patients who attended the leukodystrophy clinic at the Dana-Dwek Children's Hospital between June 2019 and December 2021 were retrieved. Clinical, molecular, and neuroimaging data were reviewed, and the diagnostic yield was compared across genetic tests. Sixty-seven patients (Female/Male ratio 35/32) were included. Median age at symptom onset was 9 months (interquartile range (IQR) 3–18 months), and median length of follow-up was 4.75 years (IQR 3–8.5). Time from symptom onset to a confirmed genetic diagnosis was 15months (IQR 11–30). Pathogenic variants were identified in 60/67 (89.6%) patients; classic leukodystrophy (55/67, 82.1%), leukodystrophy mimics (5/67, 7.5%). Seven patients (10.4%) remained undiagnosed. Exome sequencing showed the highest diagnostic yield (34/41, 82.9%), followed by single-gene sequencing (13/24, 54%), targeted panels (3/9, 33.3%) and chromosomal microarray (2/25, 8%). Familial pathogenic variant testing confirmed the diagnosis in 7/7 patients. A comparison between patients who presented before (n = 31) and after (n = 21) next-generation sequencing (NGS) became clinically available in Israel revealed that the time-to-diagnosis was shorter in the latter group with a median of 12months (IQR 3.5–18.5) vs. a median of 19 months (IQR 13–51) (p = 0.005). NGS carries the highest diagnostic yield in children with suspected leukodystrophy. Access to advanced sequencing technologies accelerates speed to diagnosis, which is increasingly crucial as targeted treatments become available. • NGS carries the highest diagnostic yield in leukodystrophy (LD). • CMA has low diagnostic yield in LD. • Access to next generation sequencing shortens time to diagnosis in LD patients. • LD frequencies differ between different geographical areas. [ABSTRACT FROM AUTHOR]

Constitutional mismatch repair deficiency (CMMRD) is a rare recessive childhood cancer predisposition syndrome caused by germline mismatch repair variants. Constitutional microsatellite instability (cMSI) is a CMMRD diagnostic hallmark and may associate with cancer risk. We quantified cMSI in a large CMMRD patient cohort to explore genotype–phenotype correlations using novel MSI markers selected for instability in blood. Three CMMRD, 1 Lynch syndrome, and 2 control blood samples were genome sequenced to >120× depth. A pilot cohort of 8 CMMRD and 38 control blood samples and a blinded cohort of 56 CMMRD, 8 suspected CMMRD, 40 Lynch syndrome, and 43 control blood samples were amplicon sequenced to 5000× depth. Sample cMSI score was calculated using a published method comparing microsatellite reference allele frequencies with 80 controls. Thirty-two mononucleotide repeats were selected from blood genome and pilot amplicon sequencing data. cMSI scoring using these MSI markers achieved 100% sensitivity (95% CI, 93.6%–100.0%) and specificity (95% CI 97.9%–100.0%), was reproducible, and was superior to an established tumor MSI marker panel. Lower cMSI scores were found in patients with CMMRD with MSH6 deficiency and patients with at least 1 mismatch repair missense variant, and patients with biallelic truncating/copy number variants had higher scores. cMSI score did not correlate with age at first tumor. We present an inexpensive and scalable cMSI assay that enhances CMMRD detection relative to existing methods. cMSI score is associated with mismatch repair genotype but not phenotype, suggesting it is not a useful predictor of cancer risk. [Display omitted] We develop an accurate blood test for a childhood cancer syndrome. The test result is influenced by what genetic change is in each patient, but does not predict cancer risk. [ABSTRACT FROM AUTHOR]

Objective: To examine the detection rate of clinically significant chromosomal microarray analysis (CMA) results in singleton pregnancies with clubfoot.Methods: Data from all CMA tests in singleton pregnancies with sonographic diagnosis of clubfoot (talipes equinovarus) performed between January 2013 and September 2017 were retrospectively obtained from the Israeli Ministry of Health computerized database. The rates of clinically significant CMA results in fetuses with clubfoot were compared to the general population risk, based on a local cohort of 5541 pregnancies with no major sonographic anomalies.Results: Of the 5750 CMA tests, a total of 269 (4.7%) were performed due to demonstration of fetal clubfoot. Of the 229 cases with isolated deformity, nine (3.9%) clinically significant CMA results were detected. This detection rate is significantly increased compared to the control population (RR 2.7 (95% CI 1.4-5.0)). In the 40 pregnancies with non-isolated clubfoot, seven (17.5%) clinically significant CMA results were detected, a significantly higher frequency compared to the control population and to isolated clubfoot cases.Discussion: Sonographic diagnosis of clubfoot, whether isolated or associated with additional sonographic defects, increases the risk for abnormal CMA findings. Thus, CMA analysis, in conjunction with thorough sonographic anatomic survey, should be recommended in such pregnancies. [ABSTRACT FROM AUTHOR]