Multiple congenital contractures (MCC) due to fetal akinesia manifest across a broad spectrum of diseases, ranging from mild distal arthrogryposis to lethal fetal akinesia deformation sequence. We hereby present a series of 26 fetuses displaying severe MCC phenotypes from 18 families and describe detailed prenatal ultrasound findings, postmortem clinical evaluations, and genetic investigations. Most common prenatal findings were abnormal facial profile (65%), central nervous system abnormalities (62%), polyhydramnios (50%), increased nuchal translucency (50%), and fetal hydrops (35%). Postmortem examinations unveiled additional anomalies including facial dysmorphisms, dysplastic skeletal changes, ichthyosis, multiple pterygia, and myopathy, allowing preliminary diagnosis of particular Mendelian disorders in multiple patients. Evaluation of the parents revealed maternal grip myotonia in one family. By exome sequencing and targeted testing, we identified causative variants in ACTC1, CHST14, COG6, DMPK, DOK7, HSPG2, KLHL7, KLHL40, KIAA1109, NEB, PSAT1, RAPSN, USP14, and WASHC5 in 15 families, and one patient with a plausible diagnosis associated with biallelic NEB variants. Three patients received a dual diagnosis. Pathogenic alterations in newly discovered genes or in previously known genes recently linked to new MCC phenotypes were observed in 44% of the cohort. Our results provide new insights into the clinical and molecular landscape of lethal MCC phenotypes.

The brittle hair syndrome Trichothiodystrophy (TTD) is characterized by variable clinical features, including photosensitivity, ichthyosis, growth retardation, microcephaly, intellectual disability, hypogonadism, and anaemia. TTD‐associated mutations typically cause unstable mutant proteins involved in various steps of gene expression, severely reducing steady‐state mutant protein levels. However, to date, no such link to instability of gene‐expression factors for TTD‐associated mutations in MPLKIP / TTDN1 has been established. Here, we present seven additional TTD individuals with MPLKIP mutations from five consanguineous families, with a newly identified MPLKIP variant in one family. By mass spectrometry‐based interaction proteomics, we demonstrate that MPLKIP interacts with core splicing factors and the lariat debranching protein DBR1. MPLKIP ‐deficient primary fibroblasts have reduced steady‐state DBR1 protein levels. Using Human Skin Equivalents (HSEs), we observed impaired keratinocyte differentiation associated with compromised splicing and eventually, an imbalanced proteome affecting skin development and, interestingly, also the immune system. Our data show that MPLKIP, through its DBR1 stabilizing role, is implicated in mRNA splicing, which is of particular importance in highly differentiated tissue.

The scope of cell-free DNA (cfDNA) testing was expanded to the genome, which allowed screening for rare chromosome anomalies (RCAs). Since the efficiency of the test for RCAs remains below the common aneuploidies, there is a debate on the usage of expanded tests. This study focuses on the confirmatory and follow-up data of cases with positive cfDNA testing for RCAs and cases with screen-negative results in a series of 912 consecutive cases that underwent invasive testing following cfDNA testing. Chorion villus sampling (CVS), amniocentesis (AS), fetal blood sampling, and term placenta samples were investigated using classical cytogenetic and molecular cytogenetic techniques. Out of 593 screen-positive results, 504 (85%) were for common aneuploidies, 40 (6.7%) for rare autosomal trisomies (RATs), and 49 (8.3%) for structural chromosome anomalies (SAs). Of the screen-positives for RATs, 20 cases were evaluated only in fetal tissue, and confined placental mosaicism (CPM) could not be excluded. Among cases with definitive results (n = 20), the rates of true positives, placental mosaics, and false positives were 35%, 45%, and 10%, respectively. Among screen-positives for SAs, 32.7% were true positives. The confirmation rate was higher for duplications than deletions (58.3% vs. 29.4%). The rate of chromosomal abnormality was 10.9% in the group of 256 screen-negatives with pathological ultrasound findings. This study provides further data to assess the efficiency of expanded cfDNA testing for RATs and SAs. The test efficiency for cfDNA seems to be higher for duplications than for deletions, which is evidence of the role of expert ultrasound in identifying pregnancies at increased risk for chromosome anomalies, even in pregnancies with screen-negatives. Furthermore, we discussed the efficiency of CVS vs. AC in screen-positives for RATs.

Background: Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder that results in a predisposition to the growth of multiple tumors in the central nervous system, the peripheral nervous system, and the skin. The clinical manifestations of neurofibromatosis are associated with loss of neurofibromin expression which causes the upregulation of the RAS pathway. Although neurofibromatosis type 1 can be diagnosed based on the National Institutes of Health criteria, sometimes the diagnosis is difficult, in cases where the characteristic features do not develop. Moreover, other RAS-related disorders may present with significantly overlapping clinical features. Aims: To determine the clinical and molecular genetic characteristics of Turkish patients with neurofibromatosis type 1. Study design: Cross-sectional study. Methods: For the genetic analysis of 27 Turkish families clinically diagnosed with NF1 between 1990 and 2019, we used a multi-step process consisting of next-generation sequencing, multiplex ligation-dependent probe amplification, and array-comparative genomic hybridization. Results: In this study, we identified 11 novel and 11 previously reported single-nucleotide variants in 22 families. Whole gene deletions were detected by multiplex ligation-dependent probe amplification analysis in 3 families. Of those, array comparative genomic hybridization analysis defined a 17q11.2 deletion in 4 patients from 2 families and 1.2-Mb involving 1 unrelated patient. All patients with a deletion had facial dysmorphism, suggesting a peculiar phenotype in this group. We could not find any pathogenic variant in the 2 families that met the National Institutes of Health criteria. Conclusion: The novel pathogenic variants identified in this study broaden the spectrum of pathogenic variants in NF1 and provide better clinical characterization of NF1. RNA-seq experiments are recommended in patients who meet the National Institutes of Health diagnostic criteria for NF but have not identified any variants in nextgeneration sequencing, multiplex ligation-dependent probe amplification, or array-comparative genomic hybridization analysis.