Risk of Clinically Significant Chromosomal Microarray Analysis Findings in Fetuses With Nuchal Translucency From 3.0 mm Through 3.4 mm.

OBJECTIVE: To examine the risk of clinically significant chromosomal microarray analysis findings in fetuses with nuchal translucency from 3.0-3.4 mm. In addition, we aimed to define the yield of noninvasive prenatal testing (NIPT) in such pregnancies. METHODS: This retrospective cohort study included results of all chromosomal microarray analysis tests performed owing to a nuchal translucency measurement from 3.0-3.4 mm, without ultrasonographic anomalies, retrieved from the Israeli Ministry of Health computerized database. Rates of clinically significant (pathogenic and likely pathogenic) microarray findings were compared with a previously published local control population, encompassing 2,752 fetuses with normal ultrasound findings and nuchal translucency less than 3.0 mm. RESULTS: Overall, 619 chromosomal microarray analyses were performed owing to isolated nuchal translucency from 3.0-3.4 mm. Of these, 29 (4.7%) cases had clinically significant copy number variants, a significantly higher risk compared with control-group pregnancies (relative risk 3.3, 95% CI 2.6-7.2). Divided by tenths of millimeters, the risk for abnormal chromosomal microarray analysis findings remained significantly increased, except for the subgroup of 198 fetuses with nuchal translucency measurements of 3.0 mm. Noninvasive prenatal testing for the five common chromosome aneuploidies would have missed 41.4% of the abnormal copy number variants-1.9% of overall cases, or 1 in 52 fetuses with nuchal translucency from 3-3.4 mm. Genome-wide NIPT, as well as traditional karyotyping, could have missed an abnormal finding in 9 of 619 (1.5%), or 1 in 69 fetuses. CONCLUSION: Our outcomes show that the rate of abnormal chromosomal microarray analysis findings in fetuses with nuchal translucency from 3.1-3.4 mm is significantly higher compared with fetuses with normal ultrasound findings.

The rare 13q33-q34 microdeletions: eight new patients and review of the literature.

The objective of this study is to shed light on the phenotype and inheritance pattern of rare 13q33-q34 microdeletions. Appropriate cases were retrieved using local databases of two largest Israeli centers performing CMA analysis. In addition, literature search in PubMed, DECIPHER and ClinVar databases was performed. Local database search yielded eight new patients with 13q33.1-q34 microdeletions (three of which had additional copy number variants). Combined with 15 cases detected by literature search, an additional 23 cases were reported in DECIPHER database, and 17 cases from ClinVar, so overall 60 patients with isolated 13q33.1-q34 microdeletions were described. Developmental delay and/or intellectual disability were noted in the vast majority of affected individuals (81.7% = 49/60). Of the 23 deletions involving the 13q34 cytoband only, in 3 cases, developmental delay and/or intellectual disability was not reported. Interestingly, in two of these cases (66.7%), the deletions did not involve the terminal CHAMP1 gene, as opposed to 3/20 (15%) of patients with 13q34 deletions and neurocognitive disability. Facial dysmorphism and microcephaly were reported in about half of the overall cases, convulsions were noted in one-fifth of the patients, while heart anomalies, short stature and hypotonia each involved about 10-30% of the cases. None of the 13q33-q34 deletions were inherited from a reported healthy parent. 13q33-q34 microdeletions are rare chromosomal aberrations, associated with high risk for neurodevelopmental disability. The rarity of this chromosomal aberration necessitates continuous reporting and collection of available evidence, to improve the ability to provide accurate genetic counseling, especially in the context of prenatal setting.

Uterine cancer in Jewish Israeli BRCA1/2 mutation carriers.

BACKGROUND: BRCA1/2 mutation carriers have an increased risk of developing ovarian cancer, leading to the recommendation of risk-reducing salpingo-oophorectomy (RRSO) at 35-40 years of age. The role, if any, that BRCA mutations play in conferring uterine cancer risk, is unresolved. METHOD: Jewish Israeli women, carriers of one of the predominant Jewish mutations in BRCA1/2 from 1998 to 2016, were recruited. Cancer diagnoses were determined through the Israeli National Cancer Registry. Uterine cancer risk was assessed by computing the standardized incidence ratio of observed-to-expected number of cases, using the exact 2-sided P value of Poisson count. RESULTS: Overall, 2627 eligible mutation carriers were recruited from 1998 to 2016, 2312 (88%) of whom were Ashkenazi Jews (1463 BRCA1, 1154 BRCA2 mutation carriers, 10 double mutation carriers). Among these participants, 1310 underwent RRSO without hysterectomy at a mean (± standard deviation) age of 43.6 years (± 4.4 years). During 32,774 women-years of follow up, 14 women developed uterine cancer, and the observed-to-expected rate of all histological subtypes was 3.98 (95% confidence interval [CI], 2.17-6.67; P < .001). For serous papillary (n = 5), the observed-to-expected ratio was 14.29 (95% CI, 4.64-33.34; P < .001), and for sarcoma (n = 4) it was 37.74 (95% CI, 10.28-96.62). These rates were also higher than those detected in a group of 1844 age- and ethnicity-matched women (53% with breast cancer). CONCLUSION: Israeli BRCA1 or BRCA2 mutation carriers are at an increased risk for developing uterine cancer, especially serous papillary and sarcoma. These elevated risks of uterine cancer should be discussed with BRCA carriers.