No abstract

Multiple congenital contractures (MCC) comprise a number of rare, non‐progressive conditions displaying marked phenotypic and etiologic heterogeneity. A genetic cause can be established in approximately half of the affected individuals, attributed to genetic defects in the formation and functioning of the central and peripheral nervous system, neuromuscular junctions, skeletal muscles, and connective tissue. Ubiquitin‐specific protease 14 (USP14) encodes a major proteasome‐associated deubiquitinating enzyme with an established dual role as an inhibitor and an activator of proteolysis, maintaining protein homeostasis. Usp14‐deficient mice show a phenotype similar to lethal human MCC phenotypes, with callosal anomalies, muscle wasting, and early lethality, attributed to neuromuscular junction defects due to decreased monomeric ubiquitin pool. We describe a new, autosomal recessive MCC phenotype in three fetuses from two different branches of a consanguineous family, presenting with distal arthrogryposis, underdevelopment of the corpus callosum, and dysmorphic facial features. Exome sequencing identified a biallelic 4‐bp deletion (c.233_236delTTCC; p.Leu78Glnfs*11, SCV002028347) in USP14, and sequencing of family members showed segregation with the phenotype. RT‐qPCR experiment in an unaffected heterozygote revealed that mutant USP14 was expressed, indicating that abnormal transcript escapes nonsense‐mediated mRNA decay. We propose that herein described fetuses represent the first human phenotype of USP14 loss, with callosal anomalies and/or cortical malformations, multiple contractures, and recognizable dysmorphic facial features.

For COVID-19 (Coronavirus Disease-2019) cases, detecting host-based factors that predispose to infection is a very important research area. In this study, the aim is to investigate the MBL2 and NOS3 gene polymorphisms in COVID-19 patients with lung involvement, whose first nasopharyngeal PCR results were negative. Seventy-nine patients diagnosed with COVID-19 between April-June 2020 who were admitted to a university hospital, and 100 healthy controls were included. In the first statistical analysis performed between PCR-positive, CT-negative and PCR-negative, CT-positive patients; the AB of MBL2 genotype was significantly higher in the first group (p = 0.049). The B allele was also significantly higher in the same subgroup (p = 0.001). The absence of the AB genotype was found to increase the risk of CT positivity by 6.9 times. The AB genotype of MBL2 was higher in healthy controls (p = 0.006). The absence of the AB genotype was found to increase the risk of CT positivity; also, it can be used for early detection and isolation of patients with typical lung involvement who had enough viral loads, but whose initial PCR results were negative.

Bi-allelic variants in Iron-Sulfur Cluster Scaffold (NFU1) have previously been associated with multiple mitochondrial dysfunctions syndrome 1 (MMDS1) characterized by early-onset rapidly fatal leukoencephalopathy. We report 19 affected individuals from 10 independent families with ultra-rare bi-allelic

Kabuki syndrome (KS) is a rare disorder characterized by distinct face, persistent fingertip pads, and intellectual disability (ID) caused by mutation in KMT2D (56%–76%) or KDM6A (5%–8%). Thirty‐seven children aged 1–16 years who followed for median of 6.8 years were included in this study, which aimed to investigate the genetic and clinical characteristics of KS patients. KMT2D and KDM6A were evaluated by sequencing and multiplex‐ligation‐dependent probe amplification in 32 patients. Twenty‐one pathogenic variants in KMT2D, of which 17 were truncated and nine were novel, one frame‐shift novel variant in KDM6A were identified. The molecular diagnosis rate was 68.7% (22/32). In the whole‐exome sequencing analysis performed in the remaining patients, no pathogenic variant that could cause any disease was detected. All patients had ID; 43.2% were severe and moderate. We observed that facial features that became more prominent with age were enough for a possible diagnosis of KS in infancy. The frequencies of facial features, cardiac and renal anomalies, short stature, microcephaly, and epilepsy did not differ depending on whether they had truncating or nontruncating variants or were in variant‐negative KS‐like group. This study has expanded clinical features of the disease, as well as identified new variants in genes causing KS.