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Sotos syndrome is a non-progressive neurological disease with overgrowing, increased bone age, and developmental retardation. The aim of this study is to evaluate the prenatal, natal, and postnatal clinical findings of patients with Sotos syndrome. Sixteen patients suspected to have Sotos syndrome with clinical findings were examined retrospectively, ranging in ages between 3 and 23. In our file screening, we screened the FISH results of all 16 patients, but not all patients had NSD1 gene analysis results. We collected NSD1 gene analysis results, if there were any. The parameters that we investigated for these patients are birth weight, birth length, Apgar score at the 5th minute, dysmorphological face appearance, bone age, seizure, learning disability, feeding difficulties, surgical operation, and other accompanying abnormalities (brain MRI, abnormal echocardiographic findings, chronic otitis media, etc.). The anamnesis, clinical examination findings, and genetic reports of the patients were examined. For this, the hospital registration system was used. Breech presentation, Apgar score in the 5th minute of between 4 and 7, atrial septal defect at echocardiography, and consanguineous marriage rate were detected to be increased in individuals with Sotos syndrome compared to the normal population. When compared to the general population, delayed psychomotor development was determined. Macrocephaly, increased bone age, chronic otitis media frequency, and hernia operation frequency were determined to see if all patients were consistent with the literature. As a result of NSD1 gene sequencing analyses (NSD1 gene analysis was performed in 6 patients and a mutation was detected in 3 of them), three were found to have NSD1 gene mutation (one of them was novel). A novel deletion-type mutation that was not previously reported in the literature in the 19th exon of the NSD1 gene was determined. Xiphoidal protrusion was detected on this patient that had the novel mutation, and this situation has not been reported in the literature previously. If a patient has rapid growth, difficulty in learning, macrocephaly, speech delay, and timid personality, Sotos syndrome can be considered at the pre-diagnosis stage.

Abstract Context Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75% to 90% of individuals with hypergonadotropic hypogonadism presenting as POI, the molecular etiology is unknown. Common etiologies include chromosomal abnormalities, environmental factors, and congenital disorders affecting ovarian development and function, as well as syndromic and nonsyndromic single gene disorders suggesting POI represents a complex trait. Objective To characterize the contribution of known disease genes to POI and identify molecular etiologies and biological underpinnings of POI. Design, Setting, and Participants We applied exome sequencing (ES) and family-based genomics to 42 affected female individuals from 36 unrelated Turkish families, including 31 with reported parental consanguinity. Results This analysis identified likely damaging, potentially contributing variants and molecular diagnoses in 16 families (44%), including 11 families with likely damaging variants in known genes and five families with predicted deleterious variants in disease genes (IGSF10, MND1, MRPS22, and SOHLH1) not previously associated with POI. Of the 16 families, 2 (13%) had evidence for potentially pathogenic variants at more than one locus. Absence of heterozygosity consistent with identity-by-descent mediated recessive disease burden contributes to molecular diagnosis in 15 of 16 (94%) families. GeneMatcher allowed identification of additional families from diverse genetic backgrounds. Conclusions ES analysis of a POI cohort further characterized locus heterogeneity, reaffirmed the association of genes integral to meiotic recombination, demonstrated the likely contribution of genes involved in hypothalamic development, and documented multilocus pathogenic variation suggesting the potential for oligogenic inheritance contributing to the development of POI. Exome sequencing was used to investigate genes and mutational mechanisms contributing to primary ovarian insufficiency, and to gain insights into disease biology and underlying pathophysiology.

MaterialLinked-read whole genome sequencing (WGS) presents a new opportunity for cost-efficient singleton sequencing in place of traditional trio-based designs while generating informative-phased variants, effective for recessive disorders when parental DNA is unavailable.MethodsWe have applied linked-read WGS to identify novel causes of Meier-Gorlin syndrome (MGORS), a condition recognised by short stature, microtia and patella hypo/aplasia. There are eight genes associated with MGORS to date, all encoding essential components involved in establishing and initiating DNA replication.ResultsOur successful phasing of linked-read data led to the identification of biallelic rare variants in four individuals (24% of our cohort) in DONSON, a recently established DNA replication fork surveillance factor. The variants include five novel missense and one deep intronic variant. All were demonstrated to be deleterious to function; the missense variants all disrupted the nuclear localisation of DONSON, while the intronic variant created a novel splice site that generated an out-of-frame transcript with no residual canonical transcript produced.ConclusionVariants in DONSON have previously been associated with extreme microcephaly, short stature and limb anomalies and perinatal lethal microcephaly-micromelia syndrome. Our novel genetic findings extend the complicated spectrum of phenotypes associated with DONSON variants and promote novel hypotheses for the role of DONSON in DNA replication. While our findings reiterate that MGORS is a disorder of DNA replication, the pathophysiology is obviously complex. This successful identification of a novel disease gene for MGORS highlights the utility of linked-read WGS as a successful technology to be considered in the genetic studies of recessive conditions.

Generalised arterial calcification of infancy, an autosomal recessive disorder characterised by abnormal calcification of medium and large-sized arteries, represents a rare cause of dilated cardiomyopathy. We present the case of a two-month-old girl diagnosed posthumously with dilated cardiomyopathy. Studies suggest that early initiation of treatment can improve prognosis in generalised arterial calcification of infancy, so clinicians should be alert to the condition, especially in patients displaying generalised narrowing of medium and large-sized arteries.

Marfan syndrome (MFS) is an autosomal dominant genetic condition that mainly affects connective tissue in many parts of the body. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. The diagnosis of MFS relies on the revised Ghent criteria, outlined by international expert opinion to facilitate accurate recognition of this syndrome as well as to improve patient management and counseling. However, it may not always be possible to make a definitive diagnosis according to these criteria in each patient and thus molecular confirmation is necessary in subjects with suspected MFS. This debilitating, if not fatal, disorder is caused by mutations in FBN1, which encodes a major constitutive element of extracellular microfibrils. Here, we present a detailed clinical and molecular analysis of 76 Turkish patients with definitive or suspected MFS diagnosed at our center between 2014 and 2019. We were able to identify a total of 51 different FBN1 variants in our cohort, 31 of which have previously been reported in the relevant scientific literature. The remaining 20 variants have not been documented to date. In one patient, we detected a large deletion including the entire FBN1 gene using the array CGH approach. Currently, there are very few studies on the genotype-phenotype correlation of patients with MFS, and no clear genotype-phenotype maps for MFS have been constructed so far, except for some cases. We believe that our findings will make a rich and peculiar contribution to the elusive genotype-phenotype relationship in MFS, especially in this large and populous ethnic group.

Leukocyte adhesion deficiency is an autosomal recessive primary immunodeficiency that has been divided into three types: LAD1 (beta-2 integrin (CD18) family deficiency/defect), LAD2 (absence of fucosylated carbonhydrate ligands for selectins) and LAD3 (defective activation of all beta integrins). However, recently LAD4 has been described in cystic fibrosis patients, with a defect in integrin activation reported in monocytes. LAD-I is the most common type and prevalence of 1 in 1,000,000 live births. Clinical features of LAD patients are recurrent bacterial and fungal infections, omphalitis with delayed umbilical stump separation, significant leukocytosis especially neutrophilia during infection periods, impaired pus formation, and delayed traumatic or surgical wound healing. Flow cytometry is considered a useful tool for rapid diagnosis of the disease. The study of CD18 and CD11 (a, b, c) expression patterns in peripheral blood leukocytes helps to distinguish different phenotypes of LAD-I. In general, patients with ≥ 2% CD18 expression tend to have a less severe infection and often survive until adulthood, whereas < 2% CD18 expression often results in death in infancy. In this case report, three siblings, 10, 15, and 17 years old, diagnosed with leukocyte adhesion defect type 1 in adolescence age group, are presented.

The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families: 1) a homozygous nonsense mutation p.Arg242* in four males with laterality defects and infertility and 2) a homozygous nonsense mutation p.Gln203* in one female with laterality defects and recurrent respiratory infections additionally carrying homozygous mutations in DNAH5. Consistent with the laterality defects observed in these individuals, we found Mns1 to be expressed in mouse embryonic ventral node. Immunofluorescence analysis further revealed that MNS1 localizes to the axonemes of respiratory cilia as well as sperm flagella in human. In-depth ultrastructural analyses confirmed a subtle outer dynein arm (ODA) defect in the axonemes of respiratory epithelial cells resembling findings reported in Mns1-deficient mice. Ultrastructural analyses in the female carrying combined mutations in MNS1 and DNAH5 indicated a role for MNS1 in the process of ODA docking (ODA-DC) in the distal respiratory axonemes. Furthermore, co-immunoprecipitation and yeast two hybrid analyses demonstrated that MNS1 dimerizes and interacts with the ODA docking complex component CCDC114. Overall, we demonstrate that MNS1 deficiency in humans causes laterality defects (situs inversus) and likely male infertility and that MNS1 plays a role in the ODA-DC assembly.

Arthrogryposis, defined as congenital joint contractures in 2 or more body areas, is a clinical sign rather than a specific disease diagnosis. To date, more than 400 different disorders have been described that present with arthrogryposis, and variants of more than 220 genes have been associated with these disorders; however, the underlying molecular etiology remains unknown in the considerable majority of these cases. We performed whole exome sequencing (WES) of 52 patients with clinical presentation of arthrogryposis from 48 different families. Affected individuals from 17 families (35.4%) had variants in known arthrogryposis-associated genes, including homozygous variants of cholinergic γ nicotinic receptor (CHRNG, 6 subjects) and endothelin converting enzyme-like 1 (ECEL1, 4 subjects). Deleterious variants in candidate arthrogryposis-causing genes (fibrillin 3 [FBN3], myosin IXA [MYO9A], and pleckstrin and Sec7 domain containing 3 [PSD3]) were identified in 3 families (6.2%). Moreover, in 8 families with a homozygous mutation in an arthrogryposis-associated gene, we identified a second locus with either a homozygous or compound heterozygous variant in a candidate gene (myosin binding protein C, fast type [MYBPC2] and vacuolar protein sorting 8 [VPS8], 2 families, 4.2%) or in another disease-associated genes (6 families, 12.5%), indicating a potential mutational burden contributing to disease expression. In 58.3% of families, the arthrogryposis manifestation could be explained by a molecular diagnosis; however, the molecular etiology in subjects from 20 families remained unsolved by WES. Only 5 of these 20 unrelated subjects had a clinical presentation consistent with amyoplasia; a phenotype not thought to be of genetic origin. Our results indicate that increased use of genome-wide technologies will provide opportunities to better understand genetic models for diseases and molecular mechanisms of genetically heterogeneous disorders, such as arthrogryposis. This work was supported in part by US National Human Genome Research Institute (NHGRI)/National Heart, Lung, and Blood Institute (NHLBI) grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, and US National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS058529 to J.R. Lupski.

AimThis study aimed to evaluate coagulation disorders in patients with argininemia associated with arginase 1 gene mutations and the control of these disorders with sodium benzoate treatment.Materials and MethodsFive argininemia patients followed up in the Pediatric Metabolism Clinic in University of Health Sciences Türkiye, Başakşehir Çam and Sakura City Hospital, were included in this study. The patients initially received protein-restricted diet treatment, while their ammonia, platelet count, liver enzymes and coagulation parameters were measured regularly. Later, sodium benzoate was added to the treatment and the same parameters were measured at 1-month intervals.ResultsIn the coagulation parameters measured after sodium benzoate treatment, one out of the five patients showed complete improvement, three had partial improvement, and one had no change. In the patients with coagulation disorders, factor VII and IX levels were low, while arginine levels remained above 250 µmol/L.ConclusionThe pathophysiology of coagulation disorders in patients with argininemia has not yet been fully elucidated, but it is thought that high arginine levels may affect the synthesis of short-lived coagulation factors. Adding sodium benzoate to dietary therapy may contribute to both the control of arginine levels and an improvement in coagulation parameters. This study demonstrates the importance of coagulation monitoring in those patients with argininemia and the potential therapeutic role of sodium benzoate.

Aim:Some recent studies on PD have focused on the WNT-2 and TGF-β1 gene loci, but its genetic basis is still not clearly known. In this context, we aimed to evaluate the presence of WNT-2 and TGF-β1 gene expression and genetic similarity between patients with Peyronie’s disease (PD) and comorbidities, especially diabetes mellitus (DM).Methods:Between May 2020 and April 2021, 57 patients diagnosed with PD were included in this cross-sectional study. The presence of comorbidities [Dupuytren’s contracture (DC), DM, hypertension (HT), dyslipidemia, and erectile dysfunction (ED)] was recorded. For genetic analysis, the WNT-2 and TGF-β1 genes were analyzed in the patients’ serum.Results:The mean age was found to be 50.2. 45.6% of the patients had DM, 19.1% had HT, 14% had dyslipidemia, 5.3% had DC, and 40.4% had ED. TGF-β1 gene expression was found to be increased in all patients; WNT-2 gene expression was found to be increased in 80.7%. When subtypes of the TGF-β1 and WNT-2 gene expression were analyzed, 52.6% of patients with WNT-2 gene expression and 95.5% of patients with TGF-β1 gene expression were found to be homozygous, and the others were found to be heterozygous. Patients with DM and PD had significantly higher homozygous WNT-2 gene expression (p=0.03). No significant relationship was found between other comorbidities and these genes.Conclusion:Homozygous WNT-2 gene expression was found to be increased in PD with DM. These data could be used to explain the genetic pathophysiology of PD in diabetic patients.