High rates of "atypical" single nucleotide polymorphism-based noninvasive prenatal screening results among consanguineous Arab American patients: A single center retrospective study.

Noninvasive prenatal screening (NIPS), using placental cell-free DNA from a maternal blood sample, is currently the most sensitive and specific screening tool for detecting common fetal aneuploidies. The aim of this study was to compare the rates of "atypical" single nucleotide polymorphism (SNP)-based NIPS results and subsequent pregnancy outcomes between Arab American and non-Arab American patients. We conducted a retrospective cohort study of pregnant Arab and non-Arab American patients who had SNP-based NIPS performed between September 2018 and January 2021 at an urban health system in Michigan. The rate of "atypical" results and other perinatal outcomes were compared between groups using descriptive statistics. "Atypical" results due to multifetal gestations, either undisclosed or unknown at time of ordering, were excluded. Five thousand eight hundred and seventy-three patients underwent SNP-based NIPS: 771 (13.1%) were identified as Arab American, 5102 (86.9%) were non-Arab American, and 49 (0.8%) patients received "atypical" results. Arab patients represented only 13.1% of patients screened (771/5873) but had a significantly higher rate of "atypical" results than non-Arab American patients (17/771 [2.2%] vs. 32/5102 [0.6%]; p < 0.001). Of the 17 Arab patients with "atypical" results, 9 (52.9%) were in known consanguineous relationships. No major congenital anomalies or chromosomal aberrations were identified for any patients who had "atypical" results, and no significant differences in other perinatal outcomes were observed between Arab and non-Arab American patients. A better understanding of the association between consanguinity and "atypical" SNP-based NIPS results would aid in appropriate test selection and interpretation and may help physicians and genetic counselors provide better perinatal counseling and follow-up care for patients in consanguineous relationships.

Recurrence Rate for Isolated Elevated Maternal Serum Alpha-Fetoprotein Levels and Pregnancy Outcomes.

Objective: To examine the rate of recurrence for elevated isolated maternal serum alpha-fetoprotein (MSAFP) and its associated adverse outcomes during a subsequent pregnancy. Materials and Methods: A retrospective cohort study of pregnant multiparous women who had elevated MSAFP levels during an initial and a subsequent pregnancy between 1994 and 2020. Results: Twenty-seven out of 344 (7.8%) women with elevated MSAFP had recurrent elevated MSAFP in a subsequent pregnancy. Four women were excluded due to missing data. Of the 23 women included, 5 (22%) had fetal growth restriction (FGR), 2 (9%) had pre-eclampsia, 9 (35%) had preterm births, and 2 (9%) had fetal death/miscarriage in their subsequent pregnancy. Looking at individual outcomes, 60% of women had recurrence of preterm labor, 33% had recurrence of fetal death, and 25% had recurrence of FGR. Conclusion: Women with elevated MSAFP levels during an initial pregnancy should be informed during preconception counseling about their risk of recurring elevated MSAFP and its associated adverse outcomes risks.

Biallelic Variants in LAMB1 Causing Hydranencephaly: A Severe Phenotype of a Rare Malformative Encephalopathy.

Case Report A 32-year-old female with a history of three prior pregnancy losses presented for genetic testing following an ultrasonography diagnosis of fetal hydranencephaly. Baby was born via C-section and was noted to have a head circumference of 48 cm, in addition to ocular and cardiac anomalies and dysmorphic features. Whole genome sequencing revealed a homozygous variant in LAMB1 gene. Discussion The pathobiogenesis of hydranencephaly is incompletely understood and is attributed to vascular, infectious, or genetic etiology. Herein we present LAMB1 as a monogenic cause of fetal hydranencephaly which was incompatible with life. Previously, LAMB1 -associated phenotype consisted of cobblestone lissencephaly and hydrocephalus, developmental delay, and seizures. Our proband expands the phenotypic spectrum of this malformative encephalopathy.

A novel SERPINA1 mutation causing serum alpha(1)-antitrypsin deficiency.

Mutations in the SERPINA1 gene can cause deficiency in the circulating serine protease inhibitor α(1)-Antitrypsin (α(1)AT). α(1)AT deficiency is the major contributor to pulmonary emphysema and liver disease in persons of European ancestry, with a prevalence of 1 in 2500 in the USA. We present the discovery and characterization of a novel SERPINA1 mutant from an asymptomatic Middle Eastern male with circulating α(1)AT deficiency. This 49 base pair deletion mutation (T379Δ), originally mistyped by IEF, causes a frame-shift replacement of the last sixteen α(1)AT residues and adds an extra twenty-four residues. Functional analysis showed that the mutant protein is not secreted and prone to intracellular aggregation.

Frequency of genomic rearrangements involving the SHFM3 locus at chromosome 10q24 in syndromic and non-syndromic split-hand/foot malformation.

Split-hand/foot malformation (SHFM), or ectrodactyly, is characterized by underdeveloped or absent central digital rays, clefts of the hands and feet, and variable syndactyly of the remaining digits. SHFM occurs as both an isolated finding and a component of many syndromes. SHFM is a heterogeneous condition caused by multiple loci, including SHFM1 (chromosome region 7q21-q22), SHFM2 (Xq26), SHFM3 (10q24), SHFM4 (3q27), and SHFM5 (2q31). Mutations in TP63 at the SHFM4 locus are known to underlie both syndromic and non-syndromic forms SHFM, but the causes of most non-syndromic SHFM cases remain unknown. The recent identification of submicroscopic tandem chromosome duplications affecting the SHFM3 locus in seven families with non-syndromic SHFM has helped to further unravel the molecular basis of this malformation. In our ongoing studies of the SHFM3 locus in 44 additional cases of syndromic and non-syndromic SHFM, we have identified similar chromosome rearrangements in eight additional cases (18%), using pulsed-field gel electrophoresis (PFGE). We have also utilized real-time quantitative PCR (qPCR) to test for the duplications. Seven of the cases with rearrangements were non-syndromic. The current findings bring the total of SHFM3-associated cases with chromosome rearrangements to 15, which constitute 29% (15 of 51) of the cases screened to date. This includes 9 of 9 cases (100%) with known linkage to the SHFM3 locus, all of whom have non-syndromic SHFM, and 6 of 42 additional cases (14%), four of whom have non-syndromic SHFM. Thus, SHFM3 abnormalities underlie a substantial proportion of SHFM cases and appear to be a more frequent cause of non-syndromic SHFM than mutations in TP63.