Contribution of genotypes in Prothrombin and Factor V Leiden to COVID-19 and disease severity in patients at high risk for hereditary thrombophilia.

Thrombotic and microangiopathic effects have been reported in COVID-19 patients. This study examined the contribution of the hereditary thrombophilia factors Prothrombin (FII) and Factor V Leiden (FVL) genotypes to the severity of COVID-19 disease and the development of thrombosis. This study investigated FII and FVL alleles in a cohort of 9508 patients (2606 male and 6902 female) with thrombophilia. It was observed that 930 of these patients had been infected by SARS-CoV-2 causing COVID-19. The demographic characteristics of the patients and their COVID-19 medical history were recorded. Detailed clinical manifestations were analyzed in a group of cases (n = 4092). This subgroup was age and gender-matched. FII and FVL frequency data of healthy populations without thrombophilia risk were obtained from Bursa Uludag University Medical Genetic Department's Exome Databank. The ratio of males (31.08%; 27.01%) and the mean age (36.85 ± 15.20; 33.89 ± 14.14) were higher among COVID-19 patients compared to non-COVID-19 patients. The prevalence of FVL and computerized tomography (CT) positivity in COVID-19 patients was statistically significant in the thrombotic subgroup (p < 0.05). FVL prevalence, CT positivity rate, history of thrombosis, and pulmonary thromboembolism complication were found to be higher in deceased COVID-19 patients (p < 0.05). Disease severity was mainly affected by FVL and not related to genotypes at the Prothrombin mutations. Overall, disease severity and development of thrombosis in COVID-19 are mainly affected by the variation within the FVL gene. Possible FVL mutation should be investigated in COVID-19 patients and appropriate treatment should be started earlier in FVL-positive patients.

Phenotypic and molecular characterization of five patients with PIK3CA-related overgrowth spectrum (PROS).

Somatic and germline PI3K-AKT-mTOR pathway pathogenic variants are involved in several segmental overgrowth phenotypes such as the PIK3CA-related overgrowth spectrum (PROS), Proteus syndrome, and PTEN hamartoma tumor syndrome. In this study, we describe five patients with PROS. We identified by high-throughput sequencing four different somatic PIK3CA pathogenic variants in five individuals. The Glu726Lys variant, which was previously reported in megalencephaly-capillary malformation-polymicrogyria (MCAP) syndrome, was identified in two patients with unclassified PROS. The Cys420Arg substitution, which was previously reported in CLOVES, was found in a patient with fibroadipose hyperplasia. Additionally, relatively rare pathogenic variants, His1047Tyr and Tyr1021Cys, were detected in two patients with MCAP. Therefore, we suggest performing deep sequencing of PIK3CA in all patients with suspected PROS, instead of targeted polymerase chain reaction for hotspot pathogenic variants.

WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.

Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, ∼70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered -1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.

Extending Phenotypic Spectrum of 17q22 Microdeletion: Growth Hormone Deficiency.

BACKGROUND: The 17q22 contiguous microdeletion syndrome is a recently described chromosomal disorder. Clinical features are heterogeneous because of variable deletion sizes. Clinical report: We present a child with delayed psychomotor development, dysmorphic features (prominent posterior rotated ears, upturned nose, thin upper lip, smooth philtrum, high palate), vesicoureteral reflux and growth hormone deficiency. 1.53 Mb loss at the 17q22 chromosome region in the proband was the responsible for the phenotype. Conclusion: In the few cases of interstitial 17q22 deletion in the literature, this is the first with growth hormone deficiency. This may contribute to the phenotypic spectrum of 17q22 microdeletion syndrome. As the reported cases increase, we believe that genotype-phenotype correlation will be better illuminated.

Cytogenetic, Molecular, and Phenotypic Characterization of a Patient with de novo Derivative Chromosome 18 and Review of the Literature.

We present a patient with a de novo derivative chromosome 18 which includes a terminal deletion of 18p and a terminal duplication of 18q accompanied by a cryptic duplication of 18p. The girl had mild dysmorphic features such as micro-retrognathia, upslanted palpebral fissures, bilateral epicanthus, high palate, low-set ears, short neck, and full cheeks. She also had an H-type tracheoesophageal fistula which required surgery. Her cognitive and motor skills were delayed. Karyotype analysis showed an additional segment on the short arm of chromosome 18. Chromosomal microarray revealed a 7.3-Mb terminal loss from 18p11.32 to 18p11.23, a 22.2-Mb terminal gain from 18q21.31 to 18q23, and a 3.9-Mb interstitial gain from 18p11.22 to 18p11.21. We hypothesize that the mother has gonadal mosaicism for normal chromosome 18, der(18)dup(p11.22p11.21), and der(18)dup(p11. 22p11.21)inv(18)(p11.22q21.31), or both the terminal del/dup and the interstitial duplication occurred simultaneously.

Primary Hypertrophic Osteoarthropathy Mimicking Juvenile Idiopathic Arthritis: A Novel SLCO2A1 Mutation and Imaging Findings.

Primary hypertrophic osteoarthropathy (PHO), also known as pachydermoperiostosis, is a rare, multisystemic, autosomal recessive condition typically presenting with digital clubbing, osteoarthropathy, and various skin manifestations. Radiographs show distinctive periosteal reaction and thickening along the long bones. PHO is caused by homozygous mutations in the HPGD gene in chromosome 4q34.1 or the SLCO2A1 gene in 3q22.1q22.2. Here, we report on a 20-year-old male with enlarged and swollen joints with arthralgia, palmoplantar hyperhidrosis, and large hands and feet with marked digital clubbing. We also present radiographic, MRI, and ultrasonographic features of the case. These clinical and imaging findings were compatible with the diagnosis of PHO, and a novel homozygous mutation, c.576C>G, p.Ile192Met, was found in SLCO2A1.

A Novel PORCN Frameshift Mutation Leading to Focal Dermal Hypoplasia: A Case Report.

Focal dermal hypoplasia (FDH), also known as Goltz-Gorlin syndrome, is a rare, multisystemic, X-linked dominant genodermatosis characterized by defective development of mesodermal and ectodermal tissues. Major clinical features of the disorder are skin manifestations, skeletal defects, and developmental eye abnormalities. FDH is caused by heterozygous mutations in the PORCN gene located at Xp11.23, and 90% of individuals with FDH are females. Here, we report a female patient with cutaneous changes, multiple eye anomalies, short stature, and ectrodactyly of the right foot. These clinical findings were compatible with the diagnosis of FDH, and a novel mutation, NM_022825.3:c.488delG was found in the PORCN gene causing a premature stop codon.

Autosomal Recessive Oculodentodigital Dysplasia: A Case Report and Review of the Literature.

Oculodentodigital dysplasia (ODDD) is a rare condition characterized by a typical facial appearance and variable findings of the eyes, teeth, and fingers. ODDD is caused by mutations in the GJA1 gene in chromosome 6q22 and inherited in an autosomal dominant manner in the majority of the patients. However, in recent clinical reports, autosomal recessive ODDD cases due to by GJA1 mutations were also described. Here, we report on a 14-year-old boy with microphthalmia, microcornea, narrow nasal bridge, hypoplastic alae nasi, prominent columnella, hypodontia, dental caries, and partial syndactyly of the 2nd and 3rd toes. These clinical findings were concordant with the diagnosis of ODDD, and a novel homozygous mutation (c.442C>T, p.Arg148Ter) was determined in the GJA1 gene leading to a premature stop codon. His phenotypically normal parents were found to be carriers of the same mutation. This is the third family in the literature in which ODDD segregates in an autosomal recessive manner.

Skin-Dominant Phenotype in a Patient with H Syndrome: Identification of a Novel Mutation in the SLC29A3 Gene.

H syndrome (OMIM 602782) is a very rare autosomal recessive genodermatosis with multisystem involvement. Hallmarks of this disorder are juvenile onset and progressive, hyperpigmented, hypertrichotic lesions with histiocytic infiltration. Associated systemic manifestations form a long list, and there is high variability between patients. In some patients, dysmorphic and other systemic features may be so subtle that the disorder may readily be mistaken as an acquired skin disease and treated as such. Herein, we report a novel homozygous c.1339G>A (p.Glu447Lys) mutation in the SLC29A3 gene in a patient with skin-dominant presentation of H syndrome. Additionally, due to the present case, double superior vena cava can be added to the list of possible cardiovascular manifestations of H syndrome.

Genetic Analysis of RASD1 as a Candidate Gene for Schizophrenia

Background: RASD1 encodes Dexamethasone-induced Ras-related protein 1 (Dexras1), a protein with a critical role in signal transduction in neurons. There is a strong suspicion that dysfunction of Dexras1 might contribute to the pathogenesis of neuropsychiatric diseases. Related to its functions in intracellular signaling pathways, Dexras1 has a potential role in the etiology of schizophrenia because of its close interaction with NOS1, NOS1AP, and NMDAR, which have previously been associated with schizophrenia. Aims: To investigate the association of RASD1 variants with schizophrenia in a selected cohort from Turkey. Study Design: A case-control study. Methods: We performed targeted sequencing for the two exons, single intron, and untranslated regions of RASD1 gene in 200 individuals with schizophrenia and 100 healthy controls of Turkish origin. Results: Two rare variants, RASD1 (NM_016084.5): c.722A>T and c*31G>A were identified in individuals with schizophrenia but not in any controls. The c.722A>T was found in a single individual with schizophrenia and is a missense heterozygous variant in the second exon of RASD1, which is extremely rare in GnomAD. The other variant, c*31G>A, which was found in another individual from this schizophrenia cohort, has not been reported previously. Seven previously identified common single nucleotide polymorphisms were also detected; however, they were not significantly associated with schizophrenia in this study cohort. Conclusion: Our findings suggest that rare variants of RASD1 might be contributing to the etiopathogenesis of schizophrenia. Further studies are needed to elucidate the underlying mechanism of this association.

Dual diagnosis of Ochoa syndrome and Niemann-Pick disease type B in a consanguineous family.

OBJECTIVES: Ochoa syndrome (UFS1; Urofacial syndrome-1) is a very rare autosomal recessive disorder caused by mutations in the HPSE2 gene that results bladder voiding dysfunction and somatic motor neuropathy affecting the VIIth cranial nerve. Niemann-Pick disease is a rare autosomal recessive lysosomal storage disorder with systemic involvement resulting from sphingomyelinase deficiency and generally occurs via mutation in the sphingomyelin phosphodiesterase-1 gene (SMPD1). CASE PRESENTATION: Here, we report a 6-year-old girl with symptoms such as urinary incontinence, recurrent urinary tract infections, peculiar facial expression, mainly when smiling, hypertelorism, constipation, incomplete closure of eyelids during sleep and splenomegaly. Homozygote mutations in two different genes responsible for two distinct syndromes were detected in the patient. Homozygous NM_000543.5:c.502G>A (p.Gly168Arg) mutation was found in the SMPD1 gene causing Niemann-Pick disease. In addition, some of the clinical features were due to a novel homozygous mutation identified in the HPSE2 gene, NM_021828.5:c.755delA (p.Lys252SerfsTer23). CONCLUSIONS: Here, we discuss about the importance of considering dual diagnosis in societies where consanguineous marriages are common. Accurate diagnosis of the patient is very important for the management of the diseases and prevention of complications.

CYP1A1, GST gene polymorphisms and risk of chronic myeloid leukemia.

PRINCIPLES: Associations between polymorphisms for genes encoding enzymes involved in biotransformation of xenobiotics and susceptibility to several cancers have been shown in several studies. The aim of the present study is to investigate the influence of cytochromes P450 (CYP450) 1A1*2C and Glutathione S-transferases (GSTs) (T1 and M1) gene polymorphisms in susceptibility to chronic myeloid leukaemia (CML). METHODS: The frequency of CYP1A1 Ile/Val alleles and of GSTT1 and GSTM1 homozygous deletions was examined in 107 patients with CML and 132 healthy controls by PCR and/or PCRRFLP methods using blood samples. RESULTS: The frequency of CYP1A1 Val allele was found to be 19.2% in CML patients and 4.4% for controls, indicating that persons carrying this allele had an increased risk of CML (OR = 5.10, 95% CI: 2.60-9.97). The frequency of individuals carrying the GSTT1 null genotype was higher among CML patients (40.2%) compared to controls (19.2%) (OR = 2.82, 95% CI: 1.58-5.05; p <0.001). Therefore, GSTT1 present genotype may be a protective factor for CML. Although GSTM1 null genotype frequency was slightly higher in the patient group (44.9%) than in the controls (42.3%), this difference was not statistically significant (OR = 1.11, 95% CI: 0.66-1.86; p = 0.693). Individuals with GSTM1 null genotypes without the T allele have a 5.981 higher risk for CML than those who have the T allele. CONCLUSIONS: This data suggests that polymorphic CYP1A1 and GSTT1 genes appear to affect susceptibility to CML.

Expression of Survivin and Its Splice Variants in Pediatric Acute Lymphoblastic Leukemia.

Aims: Survivin is involved in the inhibition of apoptosis and the regulation of cell division. In addition to wild-type survivin (survivin-wt), at least four splice variants with differential functions (ΔEx3 and 3B antiapoptotic, and 2α and 2B proapoptotic) have been identified. Survivin is highly expressed in several cancers, including hematological malignancies. Although acute lymphoblastic leukemia (ALL) is the most frequent malignancy in children, studies that investigated survivin expression in ALL are limited, and there is no study on 3B and 2α expression in ALL. Therefore the expression of survivin-wt and its splice variants was investigated in pediatric B-cell ALL patients. Materials and Methods: The expression of survivin-wt and its four splice variants was investigated by quantitative real-time polymerase chain reaction in archival RNA samples of 35 pediatric B-cell ALL patients. Patients were divided into high- and standard-risk groups according to age, white blood cell count, extramedullary involvement, and genetic risk factors; expression of survivin variants was compared between these two risk groups. Results: We found that the ratio of survivin-ΔEx3/wild type (WT) expression was higher in the low-risk group than in the high-risk group. Conclusion: Comparative analysis between the high- and low-risk B-cell ALL groups indicated that the survivin-ΔEx3/WT expression ratio could potentially be used in risk classification for pediatric B-cell ALL.

Relationship between angiotensin-converting enzyme gene polymorphism and severity of aortic valve calcification.

OBJECTIVE: To investigate the role of angiotensin-converting enzyme (ACE) gene polymorphism in patients with degenerative aortic valve calcification (AVC). PATIENTS AND METHODS: Our study consisted of 305 Turkish patients of European descent (139 male, 166 female; mean plus or minus age, 68 plus or minus 9 years) referred to our echocardiography laboratory for aortic valve evaluation between June 2, 2003, and April 29, 2005. The severity of AVC was graded from 1 to 6 by echocardiography. We used polymerase chain reaction to determine ACE gene polymorphism. RESULTS: The ACE insertion/deletion genotype distributions for the study population were in Hardy-Weinberg equilibrium (chi square equals 3.5, P equals .18). The study population was divided into 3 groups based on the severity of AVC: those with grade 1 calcification were in group 1, those with grades 2 to 4 in group 2, and those with grades 5 to 6 in group 3. Group 1 patients were significantly younger, less likely to have hypertension and diabetes, and had higher high-density lipoprotein cholesterol levels. The genotype frequencies were significantly different among groups, with the insertion/insertion genotype being less prevalent in group 3 patients. In multivariate analysis, independent predictors of severe AVC were hypertension (odds ratio [OR], 5.6; 95% confidence interval [CI], 2.8 to 11.0; P less than .001), low high-density lipoprotein cholesterol (OR, 2.7; 95 percent CI, 1.5 to 4.9; P equals .001), and the deletion/deletion and insertion/deletion vs insertion/insertion genotype (OR, 3.2; 95 percent CI, 1.5 to 7.2; P equals .004). CONCLUSION: These results suggest that ACE gene polymorphism may be associated with severe AVC.

TBX1 gene mutation screening in patients with non-syndromic Fallot tetralogy.

Fallot tetralogy (FT) is the most frequently observed conotruncal heart defect (CTHD) and accompanies 15% of the 22q11 deletion syndromes, DiGeorge/ velocardiofacial (DGS/VCFS) syndromes. TBX1 is a gene located in the 22q11 region and has a role in neural crest migration and conotruncal development. The mouse Tbx1 locus shows 98% homology with TBX1. DGS/VCFS-like aortic arch abnormalities in the mouse were attributed to deletions in this locus. The T-box region, common to both mice and humans, is part of TBX1 with proven effects on heart outflow track anomalies. The role of TBX1 in non-syndromic CTHDs is still unclear. In this study, we screened the TBX1 gene T-box region exons in 50 FT patients without 22q11 deletion and in 50 healthy volunteers. Our study did not show any disease causing mutations, but one polymorphic change. These results do not support a major role of the T-box region in the etiology of isolated FT. Furthermore, this study also confirms that mouse cardiac-development study models do not always provide an explanation for human phenotype-genotype correlations.

ACE gene deletion/deletion polymorphism may be a protective factor for respiratory distress in preterm infants.

The objective in this study was to evaluate the angiotensin converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism in premature infants with and without respiratory distress within the first 24 hours of life. Totally, 87 premature babies who were followed up in the neonatal unit were included in the study. Of these babies, 41 had respiratory distress, and constituted the patient group. The remaining 46 babies who did not have respiratory distress constituted the control group. Blood samples were obtained from the babies within the first few days of life prior to administration of any blood product. The ACE gene insertion (I) and deletion (D) polymorphism was investigated using polymerase chain reaction method. The I/I polymorphism was frequent in the patient group and the D/D polymorphism was frequent in the control group (p < 0.05). There was no relationship between the ACE gene polymorphism and hospital stay, ventilation or oxygen consumption duration of the patients. In addition, taking into consideration the gestational age, no association was found between ACE gene polymorphism and birth weights of the babies. The I/I genotype was considered a risk factor for pulmonary disorders in neonates as the I/I variant was more frequent in the neonates with respiratory distress than in healthy newborns. The ACE I/I genotype is associated with an increased risk of respiratory disorders among premature infants and the D/D genotype is a protective factor for respiratory disorders, but these infants with ACE D/D genotype might be at risk for the development of cardiovascular disorders later in life.

Alpha-1 Antitrypsin Levels and Polymorphisms in Interstitial Lung Diseases.

BACKGROUND/AIM: Alpha-1 antitrypsin deficiency may be a potential predisposing factor for interstitial lung fibrosis. We investigated alpha-1 antitrypsin levels and its polymorphisms in patients with interstitial lung disease. MATERIALS AND METHODS: A total of 103 interstitial lung disease patients were compared. RESULTS: The mean alpha-1 antitrypsin level in idiopathic interstitial pneumonia patients was 1.67 ± 0.33 g/L, and it was 1.54 ± 0.37 g/L in patients with nonidiopathic interstitial pneumonia (P = 0.13). Low alpha-1 antitrypsin levels were more frequently observed in nonidiopathic interstitial pneumonia patients compared with idiopathic interstitial pneumonia, but the difference was not statistically significant (8.9% vs. 0%, respectively, P = 0.4). In 100 patients, the normal PiMM genotype was detected, while abnormal ones (PiMZ, n = 2, 1.9%; PiMS, n = 1, 0.97%) were determined in three cases. When the frequency of alpha-1 antitrypsin polymorphism in interstitial lung disease patients was compared with the data of the healthy population, no significant difference was detected for the PiMZ and PiMS variants (P = 0.15 and P = 0.44, respectively). CONCLUSION: Lower levels of serum alpha-1 antitrypsin were more frequent in nonidiopathic interstitial pneumonia patients than idiopathic interstitial pneumonia without an increase in genetic polymorphism. The difference was not statistically significant.

Association Between N363S and BclI Polymorphisms of the Glucocorticoid Receptor Gene (NR3C1) and Glucocorticoid Side Effects During Childhood Acute Lymphoblastic Leukemia Treatment.

OBJECTIVE: Glucocorticoids (GCs) are the key drugs for the treatment of pediatric acute lymphoblastic leukemia (ALL). Herein, investigation of the relationship between the N363S and BclI polymorphisms of the GC receptor gene (NR3C1) and the side effects of GCs during pediatric ALL therapy was aimed. MATERIALS AND METHODS: N363S and BclI polymorphisms were analyzed in 49 patients with ALL treated between 2000 and 2012. The control group consisted of 46 patients with benign disorders. The side effects of GCs noted during the induction and reinduction periods were evaluated retrospectively according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: The BclI allele and genotype frequencies were found similar in the two groups. No N363S polymorphism was detected in either of the groups. During induction, dyspepsia was found more frequently in the CG than in the CC (wild-type) genotype (36.4% vs. 5.3%, p=0.018) and depression symptoms more frequent in patients with the G allele (CG+GG) than the CC genotype (39.3% vs. 10.5%, p=0.031). During reinduction, Cushingoid changes, dyspepsia, and depression symptoms were more frequent in patients with the G allele (CG+GG) than in patients with the CC genotype (48.1% vs. 17.6%, p=0.041; 29.6% vs. 0.0%, p=0.016; 40.7% vs. 11.8%, p=0.040, respectively). CONCLUSION: In our study, patients with the BclI polymorphism were found to have developed more frequent side effects. We think that the BclI polymorphism should be considered while designing individualized therapies in childhood ALL.

Investigation of SHOX Gene Mutations in Turkish Patients with Idiopathic Short Stature.

OBJECTIVE: The frequency of mutations in the short stature homeobox (SHOX) gene in patients with idiopathic short stature (ISS) ranges widely, depending mostly on the mutation detection technique and inclusion criteria. We present phenotypic and genotypic data on 38 Turkish patients with ISS and the distinctive features of 1 patient with a SHOX deletion. METHODS: Microsatellite markers (MSMs) DXYS10092 (GA repeats) and DXYS10093 (CT repeats) were used to select patients for fluorescent in situ hybridisation (FISH) analysis and to screen for deletions in the SHOX gene. The FISH analysis was applied to patients homozygous for at least one MSM. A Sanger sequencing analysis was performed on patients with no deletions according to FISH to investigate point mutations in the SHOX gene. RESULTS: One patient (2.6%) had a SHOX mutation. CONCLUSION: Although the number of cases was limited and the mutation analysis techniques we used cannot detect all mutations, our findings emphasize the importance of the difference in arm span and height when selecting patients for SHOX gene testing.