Deciphering the host genetic factors conferring susceptibility to severe COVID-19 using exome sequencing.

The COVID-19 pandemic remains a significant public health concern despite the new vaccines and therapeutics. The clinical course of acute SARS-CoV-2 infection is highly variable and influenced by several factors related to the virus and the host. Numerous genetic studies, including candidate gene, exome, and genome sequencing studies, genome-wide association studies, and other omics efforts, have proposed various Mendelian and non-Mendelian associations with COVID-19 course. In this study, we conducted whole-exome sequencing on 90 unvaccinated patients from Turkey with no known comorbidities associated with severe COVID-19. Of these patients, 30 had severe, 30 had moderate, and 30 had mild/asymptomatic disease. We identified rare variants in genes associated with SARS-CoV-2 susceptibility and pathogenesis, with an emphasis on genes related to the regulation of inflammation, and discussed these in the context of the clinical course of the patients. In addition, we compared the frequencies of common variants between each group. Even though no variant remained statistically significant after correction for multiple testing, we observed that certain previously associated genes and variants showed significant associations before correction. Our study contributes to the existing literature regarding the genetic susceptibility to SARS-CoV-2. Future studies would be beneficial characterizing the host genetic properties in different populations.

A Case of Short Stature Caused by a Mutation in the ACAN Gene.

Introduction: Aggrecanopathies are rare disorders associated with idiopathic short stature. They are caused by pathogenic changes in the ACAN gene located on chromosome 15q26. In this study, we present a case of short stature caused by mutations in the ACAN gene. Case Presentation: A 3-year-3-month-old male patient was referred to us because of his short stature. Physical examination revealed proportional short stature, frontal bossing, macrocephaly, midface hypoplasia, ptosis in the right eye, and wide toes. When the patient was 6 years and 3 months old, his bone age was compatible with 7 years of age. The patient underwent clinical exome sequencing and a heterozygous nonsense c.1243G>T, p.(Glu415*) pathogenic variant was detected in the ACAN gene. The same variant was found in his phenotypically similar father. Our patient is the second case with ptosis. Discussion: ACAN gene mutation should be considered in the differential diagnosis of patients with idiopathic short stature. The development and widespread use of next-generation sequencing technology has increased the diagnostic and treatment possibilities.

PPM1K defects cause mild maple syrup urine disease: The second case in the literature.

Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by the insufficient catabolism of branched-chain amino acids. BCKDHA, BCKDHB, DBT, and DLD encode the subunits of the branched-chain α-ketoacid dehydrogenase complex, which is responsible for the catabolism of these amino acids. Biallelic pathogenic variants in BCKDHA, BCKDHB, or DBT are characteristic of MSUD. In addition, a patient with a PPM1K defect was previously reported. PPM1K dephosphorylates and activates the enzyme complex. We report a patient with MSUD with mild findings and elevated BCAA levels carrying a novel homozygous start-loss variant in PPM1K. Our study offers further evidence that PPM1K variants cause mild MSUD.

A very rare cause of arthrogryposis multiplex congenita: a novel mutation in TOR1A.

OBJECTIVES: Arthrogryposis multiplex congenita-5 (AMC5) is an autosomal recessive disease caused by homozygous or compound heterozygous mutations in the TOR1A gene on chromosome 9q34. Congenital multiple joint contractures with microcephaly, typical facial dysmorphism, developmental delay, strabismus, tremor, and increased tone are the main characteristics defined in seven patients thus far. One third of the individuals with monoallelic mutations of the gene develop isolated early-onset dystonia (DYT1 dystonia), which is inherited in an autosomal dominant fashion, with variable expressivity and incomplete penetrance. We believe that different inheritance patterns of the same gene resulting in different phenotypes will provide an opportunity to understand other similar disease groups and different aspects of gene functions. CASE PRESENTATION: We present a case with severe arthrogryposis multiplex congenita, respiratory failure, and feeding difficulties, with additional hitherto unreported symptoms, such as spontaneous bone fracture, sliding esophageal hernia, and uterine prolapse. The patient carried a novel homozygous variant (c.835delA, p.Lys275Asnfs*3) in the TOR1A gene (NM_000113.2). CONCLUSIONS: We want to contribute to the phenotypic and genotypic spectra of this extremely rare disease.

Clinical and molecular evaluation of MEFV gene variants in the Turkish population: a study by the National Genetics Consortium.

Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disorder with recurrent fever, abdominal pain, serositis, articular manifestations, erysipelas-like erythema, and renal complications as its main features. Caused by the mutations in the MEditerranean FeVer (MEFV) gene, it mainly affects people of Mediterranean descent with a higher incidence in the Turkish, Jewish, Arabic, and Armenian populations. As our understanding of FMF improves, it becomes clearer that we are facing with a more complex picture of FMF with respect to its pathogenesis, penetrance, variant type (gain-of-function vs. loss-of-function), and inheritance. In this study, MEFV gene analysis results and clinical findings of 27,504 patients from 35 universities and institutions in Turkey and Northern Cyprus are combined in an effort to provide a better insight into the genotype-phenotype correlation and how a specific variant contributes to certain clinical findings in FMF patients. Our results may help better understand this complex disease and how the genotype may sometimes contribute to phenotype. Unlike many studies in the literature, our study investigated a broader symptomatic spectrum and the relationship between the genotype and phenotype data. In this sense, we aimed to guide all clinicians and academicians who work in this field to better establish a comprehensive data set for the patients. One of the biggest messages of our study is that lack of uniformity in some clinical and demographic data of participants may become an obstacle in approaching FMF patients and understanding this complex disease.