Fetal growth restriction (FGR) secondary to placental insufficiency and preeclampsia (PE) are associated with substantially increased childhood and adult morbidity and mortality. The long-term outcomes are related to placental aberrations and intrauterine programming. Advances in microarray technology allow high-resolution, genome-wide evaluation for DNA copy number variations - deletions and duplications. The aim of our study was to demonstrate the usefulness of microarray testing in FGR placentas. Using Affymetrix GeneChip for chromosomal microarray (CMA), we analyzed 10 placentas from pregnancies with FGR attributed to placental insufficiency; 5 with FGR below the 5th percentile and 5 from the 5th to <10th percentiles. All fetuses had normal anomaly scans and karyotypes. We also analyzed 5 third-trimester placentas from pregnancies complicated by PE with severe features and 5 from PE without severe features, all with appropriately grown fetuses. The results were compared to 10 placentas from uncomplicated pregnancies with healthy neonates. CMA analysis identified more genomic alterations in FGR (p < 0.05) and in PE (p < 0.05) placentas than in healthy controls. There was a correlation to the severity of FGR and PE. The genomic alterations were below the resolution of normal karyotyping. The altered genes are related to adult human height, stress reactions and to cellular migration, differentiation and adhesion. Though very preliminary, our data support evaluating FGR and PE placentas using CMA. Larger data sets are needed for further evaluation of the findings and their clinical implications.

Metaphyseal anadysplasia (MANDP) is a rare autosomal recessive form of skeletal dysplasia characterized by normal length at birth and transitory bowing of the legs. Although several families with MANDP have been reported, homozygous mutations in the matrix metalloproteinase type 9 (MMP9) gene have been described in only one consanguineous family, and thus the pre and postnatal phenotypic spectrum is still obscure. A clinically similar but more severe type is caused by autosomal-dominant inheritance and is caused by mutations in matrix metalloproteinase type 13 gene (MMP13). Here, we report the prenatal and early postnatal course of two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses suggesting a diagnosis of MANDP. We propose that MANDP should be considered in pregnancies with early prenatal shortening of the long bones without associated finding of lethal skeletal dysplasias. In addition, the finding of homozygous mutation in non-consanguineous parents of Jewish-Caucasus ancestry may suggest unawareness of such relation or the occurrence of a founder mutation in this gene.

IntroductionHyper IgE syndromes (HIES) are a group of rare primary immunodeficiency characterized by high levels of serum IgE, cold abscesses, pulmonary infections, and eczema. ZNF341 deficiency was described in 2018 in 11 patients clinically diagnosed previously with HIES. Eight of those patients, all offspring of consanguineous couples, are from three families who live in a Muslim village in Israel which has approximately 15,000 residents.ObjectiveOur study aimed to evaluate the prevalence of ZNF341 mutation in the population of the village.MethodsThree hundred DNA samples of females were included in the study. The samples belong to females that were referred to the Meir Medical Center for prenatal genetic testing before pregnancy, during 2017-2019: 200 samples were from the village, and 100 samples of Muslim females were from other villages.All samples were tested by Sanger sequencing for the ZNF341 mutation (c.904C&gt;T, NM_001282933.1).ResultsHeterozygous nonsense mutation in ZNF341 was found in ten samples (5%) of the study group compared to zero in the control group (p&lt;0.01).ConclusionThe carrier frequency of the mutation in ZNF341 in the studied village population is 1:20. This high frequency is probably due to founder mutation and consanguineous marriages.

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.

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