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Introduction: Ciliopathies with major skeletal involvement embrace a group of heterogeneous disorders caused by pathogenic variants in a group of diverse genes. A narrow thorax with shortening of long bones inspires a clinical entity underlined by dysfunction of primary cilia. Currently, more than 23 genes are listed in the OMIM database corresponding to this clinical entity: WDR19/34/35/60, IFT43/52/80/81/140/172, DYNC2LI1, TTC21B, DYNLT2B, EVC2, EVC, INTU, NEK1, CEP120, DYNC2H1, KIAA0586, SRTD1, KIAA0753, and SRTD12. Recently, individuals with biallelic loss-of-function variants in GRK2 are shown to demonstrate a phenotype compatible with Jeune syndrome. Experimental evidence has shown that impaired function of GRK2 compromises cilia-based signaling of Hedgehog pathway as well as Wnt signaling, while cilia morphology remains intact. Hence, GRK2 is now considered an essential protein in regulation of the skeletogenesis., Case Presentation: We presented a female infant born to a consanguineous marriage who was found to have a biallelic p.R474* alteration in GRK2 in reanalysis of the whole-exome sequencing (WES) data. The patient was exhibiting major clinical features of Jeune syndrome, such as shortened long bones, ribs, and narrow thorax., Discussion: Our reanalysis of WES data revealed a likely pathogenic biallelic variant in the GRK2 which is probably responsible for the Jeune syndrome phenotype in the patient. Hence, our report supports the recently discovered association of GRK2 loss-of-function variants with Jeune syndrome phenotype and emphasizes the significance of reanalysis of WES data, notably in patients with phenotypes suggestive of a such discernible Mendelian disorder., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 S. Karger AG, Basel.)

Aim: This study aims to determine the frequency of germline BRCA 1/2 mutations in Turkish women with epithelial ovarian cancer (EOC) and evaluate its relationship with clinicopathological characteristics., Methods: In this cross-sectional study, all women with recently diagnosed EOC presenting to Zekai Tahir Burak Women's Health Training and Research Hospital Medical Oncology Clinic between 2016 and 2019 were referred for BRCA testing. Peripheral blood samples were obtained from 76 patients applying to Medical Genetics and BRCA1/2 genes were sequenced using next-generation sequencing. The American College of Medical Genetics and Genomics 2015 criteria were followed for classification of genetic variants., Results: Twenty-four women (31.6%) had pathogenic germline BRCA1/2 mutations. Of these, 17 patients (22.4%) harbored germline BRCA1 mutations and 7 (9.2%) had BRCA2 mutations. When we compared the patients with and without BRCA mutations, there was significant difference in terms of family history (41.7% vs 9.6%, respectively, P = .001). Among all patients, 15 (19.7%) had history of breast or ovarian cancer in first- or second-degree relatives. Germline BRCA1/2 mutations were detected in 66.7% of patients with family history, while these mutations were found in 22.9% of patients without family history (P = .001)., Conclusion: In this sample 31.6% of Turkish women with EOC harbored germline BRCA1/2 mutations, which seems higher compared to other ethnic groups except for the Ashkenazi Jews population. All women with EOC should be referred for BRCA testing regardless of family history, age at diagnosis, and histological subtype., (© 2021 John Wiley & Sons Australia, Ltd.)

Neurodevelopmental disorders (NDDs) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDDs is > 3%, resulting in significant sociocultural and economic challenges to society. With recent advances in family-based genomics, rare-variant analyses, and further exploration of the Clan Genomics hypothesis, there has been a logarithmic explosion in neurogenetic "disease-associated genes" molecular etiology and biology of NDDs; however, the majority of NDDs remain molecularly undiagnosed. We applied genome-wide screening technologies, including exome sequencing (ES) and whole-genome sequencing (WGS), to identify the molecular etiology of 234 newly enrolled subjects and 20 previously unsolved Turkish NDD families. In 176 of the 234 studied families (75.2%), a plausible and genetically parsimonious molecular etiology was identified. Out of 176 solved families, deleterious variants were identified in 218 distinct genes, further documenting the enormous genetic heterogeneity and diverse perturbations in human biology underlying NDDs. We propose 86 candidate disease-trait-associated genes for an NDD phenotype. Importantly, on the basis of objective and internally established variant prioritization criteria, we identified 51 families (51/176 = 28.9%) with multilocus pathogenic variation (MPV), mostly driven by runs of homozygosity (ROHs) - reflecting genomic segments/haplotypes that are identical-by-descent. Furthermore, with the use of additional bioinformatic tools and expansion of ES to additional family members, we established a molecular diagnosis in 5 out of 20 families (25%) who remained undiagnosed in our previously studied NDD cohort emanating from Turkey., Competing Interests: Declaration of interests J.R.L. has stock ownership in 23andMe, is a paid consultant for the Regeneron Genetics Center, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics (BG) Laboratories. J.R.L. serves on the Scientific Advisory Board of BG. Other authors have no potential conflicts to report., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Congenital anomalies are seen at 1-3% of the population, probabilities of which are tried to be found out primarily through double, triple and quad tests during pregnancy. Also, ultrasonographical evaluations of fetuses enhance detecting and defining these abnormalities. About 60-70% of the anomalies can be diagnosed via ultrasonography, while the remaining 30-40% can be diagnosed after childbirth. Medical diagnosis and prediction is a topic that is closely related with e-Health and machine learning. e-Health applications are critically important especially for the patients unable to see a doctor or any health professional. Our objective is to help clinicians and families to better predict fetal congenital anomalies besides the traditional pregnancy tests using machine learning techniques and e-Health applications., Methods: In this work, we developed a prediction system with assistive e-Health applications which both the pregnant women and practitioners can make use of. A performance comparison (considering Accuracy, F1-Score, AUC measures) was made between 9 binary classification models (Averaged Perceptron, Boosted Decision Tree, Bayes Point Machine, Decision Forest, Decision Jungle, Locally-Deep Support Vector Machine, Logistic Regression, Neural Network, Support Vector Machine) which were trained with the clinical dataset of 96 pregnant women and used to process data to predict fetal anomaly status based on the maternal and clinical data. The dataset was obtained through maternal questionnaire and detailed evaluations of 3 clinicians from RadyoEmar radiodiagnostics center in Istanbul, Turkey. Our e-Health applications are used to get pregnant women's health status and clinical history parameters as inputs, recommend them physical activities to perform during pregnancy, and inform the practitioners and finally the patients about possible risks of fetal anomalies as the output., Results: In this paper, the highest accuracy of prediction was displayed as 89.5% during the development tests with Decision Forest model. In real life testing with 16 users, the performance was 87.5%. This estimate is sufficient to give an idea of fetal health before the patient visits the physician., Conclusions: The proposed work aims to provide assistive services to pregnant women and clinicians via an online system consisting of a mobile side for the patients, a web application side for their clinicians and a prediction system. In addition, we showed the impact of certain clinical data parameters of pregnant on the fetal health status, statistically correlated the parameters with the existence of fetal anomalies and showed guidelines for future researches., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Development of the human nervous system involves complex interactions among fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families and homozygous loss-of-function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: Androgen receptor (AR) gene mutations are the leading cause of 46,XY disorders of sex development (DSD) and are associated with varying degrees of androgen insensitivity. The aim of this study is to investigate AR gene mutations in 46,XY DSD patients with normal testosterone secretion, either normal or high testosterone/dihydrotestosterone (T/DHT) ratio and normal SRD5A2 gene analysis, collectively, suggestive of androgen insensitivity syndrome (AIS)., Methods: We direct sequenced all eight exons of the AR gene in 21 index patients with varying degrees of undervirilization., Results: We detected AR gene alterations in five patients. In patients with complete AIS we found p.Val30Met in exon 1 and p.Gly689* in exon 4. One patient with partial AIS had p.Gln712Glu in exon 4. In two patients with partial phenotype, we found common p.Glu213Glu (c.639G>A) SNP, and an additional p.Ile817Ile (c.2451T>C) mutation was found in one of these two patients., Discussion: Despite the fact that T/DHT ratio is frequently used in diagnosis of AIS, lack of precisely determined cutoffs compromises correct diagnosis. Hence, depending on clinical and biochemical findings solely may delay correct diagnosis. Direct sequence analysis of the AR is essential for precise diagnosis of AIS.

We report on a 32-year-old woman who presented at gestational age of 14 weeks. During ultrasonographic examination, we discovered that her fetus had several important abnormalities, including a cystic hygroma, craniofacial defects (low-set ears, broad nose), heart defects (single atrium, single ventricle), agenesis of corpus callosum, limb defects (clenched hands, pes equinovarus). Chorionic villus sampling and karyotyping revealed diploid/tetraploid mosaicism with trisomy 18 (mixoploidy; 4n+18/2n+18). Her second pregnancy was terminated because of the same clinical manifestations 1 year prior. Her first pregnancy resulted in the birth of an entirely healthy boy. As far as know, no other similar case has been presented in the literature., (© 2015 Wiley Periodicals, Inc.)

Donohue syndrome (DS) is characterized by severe insulin resistance due to mutations in the insulin receptor (INSR) gene. To identify molecular defects contributing to metabolic dysregulation in DS in the undifferentiated state, we generated mesenchymal progenitor cells (MPCs) from induced pluripotent stem cells derived from a 4-week-old female with DS and a healthy newborn male (control). INSR mRNA and protein were significantly reduced in DS MPC (for β-subunit, 64% and 89% reduction, respectively, P < .05), but IGF1R mRNA and protein did not differ vs control. Insulin-stimulated phosphorylation of INSR or the downstream substrates insulin receptor substrate 1 and protein kinase B did not differ, but ERK phosphorylation tended to be reduced in DS (32% decrease, P = .07). By contrast, IGF-1 and insulin-stimulated insulin-like growth factor 1 (IGF-1) receptor phosphorylation were increased in DS (IGF-1, 8.5- vs 4.5-fold increase; INS, 11- vs 6-fold; P < .05). DS MPC tended to have higher oxygen consumption in both the basal state (87% higher, P =.09) and in response to the uncoupler carbonyl cyanide-p-triflouromethoxyphenylhydrazone (2-fold increase, P =.06). Although mitochondrial DNA or mass did not differ, oxidative phosphorylation protein complexes III and V were increased in DS (by 37% and 6%, respectively; P < .05). Extracellular acidification also tended to increase in DS (91% increase, P = .07), with parallel significant increases in lactate secretion (34% higher at 4 h, P < .05). In summary, DS MPC maintain signaling downstream of the INSR, suggesting that IGF-1R signaling may partly compensate for INSR mutations. However, alterations in receptor expression and pathway-specific defects in insulin signaling, even in undifferentiated cells, can alter cellular oxidative metabolism, potentially via transcriptional mechanisms.

Partial trisomy 4q is a rare chromosomal abnormality which results in variable clinical features, often including growth and developmental delay, mental retardation and dysmorphic features. We herein report a newborn with the diagnosis of partial trisomy 4q with Hirschsprung's disease who was monitored in neonatal intensive care unit. This is the first report of partial trisomy 4q27q35 with accompanying Hirschsprung's disease.

The chondroitin sulfate proteoglycans (CSPGs) aggrecan, versican, and brevican are large aggregating extracellular matrix molecules that inhibit axonal growth of the mature central nervous system (CNS). ADAMTS proteoglycanases, including ADAMTS4 and ADAMTS5, degrade CSPGs, representing potential targets for ameliorating axonal growth-inhibition by CSPG accumulation after CNS injury. We investigated the proteolysis of CSPGs in mice homozygous for Adamts4 or Adamts5 null alleles after spinal cord injury (SCI). ADAMTS-derived 50-60 kDa aggrecan and 50 kDa brevican fragments were observed in Adamts4-/-, Adamts5-/-, and wt mice but not in the sham-operated group. By contrast Adamts4-/- and Adamts5-/- mice were both protected from versican proteolysis with an ADAMTS-generated 70 kDa versican fragment predominately observed in WT mice. ADAMTS1, ADAMTS9, and ADAMTS15 were detected by Western blot in Adamts4-/- mice' spinal cords after SCI. Immunohistochemistry showed astrocyte accumulation at the injury site. These data indicate that aggrecan and brevican proteolysis is compensated in Adamts4-/- or Adamts5-/- mice by ADAMTS proteoglycanase family members but a threshold of versican proteolysis is sensitive to the loss of a single ADAMTS proteoglycanase during SCI. We show robust ADAMTS activity after SCI and exemplify the requirement for collective proteolysis for effective CSPG clearance during SCI.

Pure partial trisomy 4q syndrome in a child with der(9)ins(9;4)(q34.3;q26q35.2)mat: Partial trisomy 4q is a rare chromosomal abnormality and mostly results from unbalanced inheritance of balanced parental chromosomal translocations. Here, we present a 5-year-old boy with partial trisomy 4q who exhibited distinctive features of 'pure' partial trisomy 4q syndrome including moderate mental and growth retardation, microcephaly, peculiar face appearance, tooth anomaly, cleft palate, language handicap, preaxial polydactyly, and urogenital anomaly. Karyotype analysis of the child revealed der(9)ins(9;4)(q34.3;q26q35.2) inherited from mother carrying ins(9;4)(q34.3;q26q35.2) resulting in trisomy of the 4q26qter segment. Whole chromosome painting, locus specific, and subtelomeric FISH analysis in mother proved that q26qter of the chromosome 4 segment was directly inserted into the telomeric sequence in chromosome 9, and depending on nature of the rearrangement in mother, karyotype of the child was determined to be pure partial 4q trisomy. This is the first report of this kind of rearrangement causing pure partial trisomy 4q with accompanying white matter change demonstrated by MRI and bilateral preaxial polydactyly of both hands.

ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) proteinases are involved in a variety of biological processes such as angiogenesis, cancer and arthritis. ADAMTSs appears to be responsible for the cleavage of proteoglycans in several tissues including brain and cartilage. Chondroitin sulfate proteoglycans (CSPGs) maintains the integrity of the brain extracellular matrix and major inhibitory contributors for glial scar and neural plasticity. The activity of aggrecanases in the central nervous system (CNS) has been reported. ADAMTSs are an enzyme degrading CSPGs in the brain. However, there is a little knowledge regarding ADAMTSs in the CNS. We investigated the expression levels of ADAMTSs mRNAs by RT-PCR after spinal cord injury in mouse. Transcripts encoding 4 of the 19 known ADAMTSs were evaluated in the mouse spinal cord following injury. ADAMTS1, -5 and -9 expression levels were found to be upregulated. No change was observed in ADAMTS4 expression. By means of immunohistochemistry, ADAMTSs were detected in the astrocytes implying its cellular source in SCI. Western blot analyses indicated that aggrecanase-generated proteoglycan fragments are produced after SCI., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)