Large scale population screening for Duchenne muscular dystrophy-Predictable and unpredictable challenges.

OBJECTIVE: Large deletions and duplications account for 65%-80% of pathogenic Duchenne muscular dystrophy (DMD) variants. A nationwide carrier screening for DMD was initiated in Israel in 2020. We assessed the carrier rate and spectrum of variants detected in a cohort of women screened for DMD carrier status and analyzed screening efficacy and challenges related to DMD population screening. METHODS: A cohort of 12,362 women were tested at a single institute using multiplex ligation-dependent probe amplification based copy number analysis of the 79 DMD exons. Consecutive sequencing of the primer region was performed when a single exon deletion was suspected. RESULTS: Deletions involving multiple exons were detected in seven cases and duplications involving multiple exons were found in four. Of these, nine were pathogenic based on previous reports and familial segregation testing, translating to a carrier rate of 1:1374. A family history was reported in three cases. Single exon deletions were suspected in 81 cases; further sequencing detected a single nucleotide variant affecting probe hybridization. These cases clustered according to ethnic origin. DISCUSSION: Population screening for DMD has a significant yield. Most carriers did not report a family history of dystrophinopathies. Screening should be adjusted for methodological limitations. Some cases may require extensive genetic counseling and work-up.

Prenatal diagnosis of a likely pathogenic variant in ZBTB18: Natural evolution of fetal phenotype including the long bones and corpus callosum.

Pathogenic variants in ZBTB18 gene have been described only postnatally with a variable phenotypic spectrum that includes intellectual disability, microcephaly, hypotonia, poor growth, corpus callosum abnormalities, seizures, and dysmorphic facial features. These features overlap with the phenotype of 1q43-q44 deletion syndrome (OMIM #612337). There are several genes within the 1q43-q44 deletion region, and ZBTB18 is of particular interest due to its known involvement in neuronal differentiation and migration. We describe here a fetus presenting with an intrauterine growth restriction, diminished long bones growth, single umbilical artery, and a short corpus callosum. On mid pregnancy ultrasound, all biometric parameters including the corpus callosum were relatively small but still within the normal range. Only a targeted follow-up during the third trimester, including neurosonographic and MRI exams, revealed the full extent of the malformation, leading to amniocentesis and a genetic workup that led to the identification of a de novo likely pathogenic variant in ZBTB18 gene. This is the first description of the evolving phenotype of a ZBTB18-related disorder in a fetus, which emphasizes the challenging diagnosis of subtle findings, that mandates a high level of clinical suspicion and a targeted follow-up throughout pregnancy.

The impact of third-trimester genetic counseling.

OBJECTIVE: To evaluate the impact of genetic counseling (GC) during the third trimester by analyzing changes in pregnancy management and the correlation with postnatal findings. METHODS: This was a retrospective study. Pregnancy course and neonatal follow-up were analyzed according to the reason for referral and implementation of recommendations. RESULTS: The records of neonates born to 181 women were retrieved. Fifty-two women (group 1-29%) qualified for pregnancy termination under Israeli guidelines and laws, and 129 (group 2-71%) were not at the time they were referred. By another division: 104 women (group 3-57%) followed the physician's diagnostic recommendations completely after counseling including amniocentesis, fetal MRI, targeted ultrasound scans, fetal echocardiography. Seventy-seven declined amniocentesis (group 4-43%). Additional abnormalities were detected postpartum in all groups without statistically difference: 3/52 (10%) in group 1, 9/129 (7%) in group 2, 6/104 (6%) in group 3, and 6/77 (8%) in group 4). CONCLUSION: GC in the third trimester of pregnancy provided the couple with a sharper more focused picture and assisted them to perceive the significance of new, significant fetal findings which attest to the value of the GC.

Cancer risks in Jewish male BRCA1 and BRCA2 mutation carriers.

Cancer risks and tumor types in male BRCA1 and BRCA2 mutation carriers are still unsettled. Cancer risks in men who were found to harbor a BRCA1 (n = 150) or a BRCA2 (n = 88) mutation or both (n = 2) were assessed by cross referencing with data on cancer occurrence in the Israeli National Cancer Registry. Incidence rates in mutation carriers were compared with men who were counseled, genotyped, and found not to harbor the familial mutation (true negative n = 122), and with standardized incidence rates (SIRs). Of 210 cancer-free individuals at initial counseling, 11 cancers were diagnosed after a mean follow-up of 5.06 ± 4.1 years (1064 person/years) compared with 1/122 in a BRCA true-negative man. The SIR for all BRCA1/2 mutation carriers compared with the rates in the general population were elevated for pancreatic cancer [2.97 (95 % CI 1.83-4.29)] and breast cancer [16.44 (95 % CI 9.65-26.24)]. For prostate cancer these rates were 0.59 (95 % CI 0.4-0.84). Jewish BRCA1/2 mutation carriers are at an increased risk for breast and pancreatic, but not prostate cancer. These cancer risks and the consequent recommendations, if validated, should be transmitted to carriers at test result disclosure.