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Ciliopathies are a heterogeneous group of diseases that are observed after deterioration of the ciliary structures on the cell surface that facilitate communication with the environment. Both liver and kidney involvement are frequently observed in this disease. Recently, a doublecortin domain containing protein 2 (DCDC2) mutation in a ciliopathy disease group was identified. Here, we present 2 patients with this mutation and with neonatal cholestasis and renal involvement.

Background/aim: Prenatal diagnosis is vital to obtain healthy generation for risky pregnancies. There have been several approaches, some of which are routinely applied in clinics to evaluate the possible prenatal deficiencies and/or diseases. In the present study, we aimed to isolate the fetal cells from endocervical samples and try to identify possible anomalies which were proved by Amniocentesis (AS) and chorionic villus sampling (CVS) methods. Materials and methods: Endoservical specimens were collected from 100 pregnant women. Cells were separated in parallel by fluorescence-activated cell sorting (FACS) and magnetic-activated cell sorting (MACS) using human leukocyte antigen (HLA) G233 and placental alkaline phosphatase (PLAP) antibodies. CMA (comprehensive meta-analysis) were carried out and male fetuses were confirmed with Sex determining region Y (SRY) amplification. Results: The percent of HLA G233 and placental and placental alkaline phosphatase (PLAP) positive cells were 4.55% and 84.59%, respectively. The percent of cells positive for both markers was 14.75%. CMA analyses were not informative. (SRY) was amplified in 67% of the samples. Conclusion: However, the success rate of the both cell sorting and scanning of DNA anomalies by aCGH and/or RT-PCR was limited, preventing the applicability of this proposal in the clinics. Still, the success of the proposed method depends on the development of the novel fetal cell-specific antibodies and the improvements in the sorting systems.

Background Copy number variants (CNVs) play a key role in the etiology of autism spectrum disorder (ASD). Therefore, recent guidelines recommend chromosomal microarrays (CMAs) as first-tier genetic tests. This study's first aim was to determine the clinical usefulness of CMAs in children diagnosed with ASD in a Turkish population. The second aim was to describe the CNVs and clinical phenotypes of children with ASD. Methods and Results This was a single-center retrospective cross-sectional study. Data were obtained from the medical records of children with ASD followed at Gazi University Hospital, (Ankara, Turkey). The sample consisted of 47 ASD cases (mean age: 60.34 +/- 25.60 months; 82.9% boys). The diagnostic yield of the CMAs was 8.5%. Four pathogenic CNVs were identified: 9p24.3p24.2 deletion, 15q11-q13 duplication, 16p11.2 deletion, and 22q13.3 deletion. Also, four variants were found at 2q36.3, 10p11.21, 15q11.2, and Xp11.22, which were classified as variants of uncertain significance (VUS). Conclusions The TRAP12 and PARD3 genes in CNVs classified as VUS may be worth investigating for autism. The initial identification of both clinical and biological markers can facilitate monitoring, early intervention, or prevention and advance our understanding of the neurobiology underlying ASD.

Warburg micro syndrome (WARBM) is a rare autosomal recessive disorder characterized by microcephaly, cortical dysplasia, intellectual disability, ocular abnormalities, spastic diplegia, and microgenitalia. WARBM has 4 subtypes arising from pathogenic variants in 4 genes (RAB18, RAB3GAP1, RAB3GAP2, and TBC1D20). Here, we report on a patient with a homozygous pathogenic c.665delC (p.Pro222HisfsTer30) variant in the RAB3GAP1 gene identified by whole-exome sequencing (WES) analyses. Only his father was a heterozygous carrier, and homozygosity mapping analysis of the WES data revealed large loss-of-heterozygosity regions in both arms of chromosome 2, interpreted as uniparental isodisomy. This uniparental disomy pattern could be due to paternal meiosis I nondisjunction because of the preserved heterozygosity in the pericentromeric region. This report provides novel insights, including a rare form of UPD, usage of homozygosity mapping analysis for the evaluation of isodisomy, and the first reported case of WARBM1 as a result of uniparental isodisomy.

Marfan syndrome (MS), a connective tissue disorder that affects ocular, skeletal, and cardiovascular systems, is caused by heterozygous pathogenic variants in FBN1. To date, over 1800 different pathogenic variants have been reported.In the present study, FBN1 sequence analysis was performed in a family and two unrelated patients with MS.Three novel pathogenic variants were detected. Two of these variants [c.6610TC; p.(Cys2204Arg) and c.1956TG; p.(Cys652Trp)], which affect a cysteine residue, were associated with MS with ectopia lentis, whereas the mutation causing a premature stop codon [c.2506delA; p.(Ser836ValfsX10)] leads to a classical MS of a milder phenotype.We anticipate that the three novel pathogenic variants identified in this study will provide further support for the clinical relevance of variants in the large FBN1 gene.

Roberts/SC phocomelia syndrome (RBS/SC) is a rare autosomal recessive inherited condition characterized by prenatal-onset growth retardation, craniofacial anomalies, and symmetrical limb reduction defects. Here, we present two affected siblings with RBS/SC who have consanguineous parents. Both patients had intrauterine growth retardation; similar facial findings, including arched eyebrows, epicanthic folds, posteriorly angulated ears, and retrognathia; and hypopigmented patches on their skin. However, despite these common findings, the extremity involvement was different between the patients. The more severely affected boy had hypoplasia of the tibia and symmetrical agenesis of the radius, ulna, proximal carpal bones, and fibula. The slightly affected girl presented with mild symmetrical mesomelic shortening. The cytogenetic analysis showed aneuploidies at varying rates concerning different chromosomes in the analyses of different culture materials. As a remarkable finding in the cytogenetic studies, chromosome analysis of fibroblast cultures obtained from the hypopigmented skin region showed a much higher frequency of aneuploidy, especially trisomy 7, than normopigmented skin fibroblasts and lymphocyte cultures for both patients, which was also proven ex vivo by qPCR analyses from uncultured skin tissues. In the subsequent ESCO2 gene sequence analysis, both patients were found to be homozygous for the mutation c.1111dupA (p.Thr371Asnfs*32; NM_001017420.2), which is known to be pathogenic. In the literature search, only two RBS/SC patient reports with hypopigmented skin patches could be found. In addition, the presence of pigmentation defects in the embryo was reported in some different animal models for RBS/SC. When the literature review and study are evaluated together, hypopigmented patches can be considered as a rare finding for RBS/SC. It can be suggested that somatic aneuploidies seen in the natural course of the disease, especially aneuploidy of chromosome 7, which has many genes associated with pigmentation, may be responsible for the hypopigmentation patches.

Campomelic dysplasia (CD, OMIM #114290) is an autosomal dominant and severe skeletal dysplasia which is characterised by the congenital shortness and bowing of the long bones (i.e., campomelia), hy...

The 46,XX ovotesticular disorder of sex development (DSD) is rarely observed in humans. This disorder is generally described as ambiguous genitalia with the presence of ovarian and testicular tissues in different gonads or in the same gonad. Almost no subjects with 46,XX ovotesticular DSD have sex-determining region of the Y chromosome (SRY) gene. It is known that excessive expression of SRY-related high mobility group box 9 (SOX9) is the cause of SRY-negative 46,XX ovotesticular DSD in the absence of SRY. Here, we analyzed our SRY-negative case with 46,XX ovotesticular DSD. In an array comparative genomic hybridization study using a peripheral blood sample from the patient, a duplication of 1114 kb (Hg19 coordinates: chr17:69006280-70120619) in the region of 17q24.3 containing SOX9 was detected. This is the first case reported from Turkey, exhibiting SOX9 duplication in SRY-negative 46,XX ovotesticular DSD.

Oculoectodermal syndrome (OES) and encephalocraniocutaneous lipomatosis (ECCL) are rare disorders that share many common features, such as epibulbar dermoids, aplasia cutis congenita, pigmentary changes following Blaschko lines, bony tumor-like lesions, and others. About 20 cases with OES and more than 50 patients with ECCL have been reported. Both diseases were proposed to represent mosaic disorders, but only very recently whole-genome sequencing has led to the identification of somatic KRAS mutations, p.Leu19Phe and p.Gly13Asp, in affected tissue from two individuals with OES. Here we report the results of molecular genetic studies in three patients with OES and one with ECCL. In all four cases, Sanger sequencing of the KRAS gene in DNA from lesional tissue detected mutations affecting codon 146 (p.Ala146Val, p.Ala146Thr) at variable levels of mosaicism. Our findings thus corroborate the evidence of OES being a mosaic RASopathy and confirm the common etiology of OES and ECCL. KRAS codon 146 mutations, as well as the previously reported OES-associated alterations, are known oncogenic KRAS mutations with distinct functional consequences. Considering the phenotype and genotype spectrum of mosaic RASopathies, these findings suggest that the wide phenotypic variability does not only depend on the tissue distribution but also on the specific genotype.

Background: Birt-Hogg-Dube syndrome (BHDS) is an autosomal dominant disease characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax; its cause is a heterozygous mutation in the FLCN gene. Colorectal polyps and carcinoma have also been reported in BHDS. FLCN mutations can be detected in patients with isolated primary spontaneous pneumothorax (PSP), so PSP may present as part of BHDS. The aim of this report is to enhance awareness that patients presenting with spontaneous PSP should be evaluated for FLCN mutations. Materials and Methods: A 44-year-old woman with PSP and her parents were analyzed for FLCN mutations. One of the patient's paternal aunts had a PSP and two of her paternal aunts had colon cancer diagnosed at early ages. Results: A novel in-frame deletion in the FLCN gene, c.932_933delCT (P311Rfs*78), was detected in the proband and in her unaffected father. Conclusions: We recommend that molecular analysis of the FLCN gene be performed in patients with PSP and their families, and that mutation carriers be examined for kidney and colon tumors.

Chromosome 8p inverted duplication deletion syndrome [inv dup del(8p)] is a rare disease characterized by intellectual disability, congenital heart defects, central nervous system abnormalities, and dysmorphic features. To date, the chromosomal alterations have been presented at the molecular level in only a small number of prenatal cases. Here, we report two prenatal cases, one with increased nuchal translucency, cerebellar vermis agenesis, a solitary interhemispheric cyst, and ventricular septal defect (VSD) and the other with VSD and discordance between right and left heart ventricles. Conventional cytogenetic, fluorescence in situ hybridization (FISH), and array comparative genomic hybridization (array CGH) analyses revealed that both cases had inv dup del(8p). This presented as a deletion larger than 6.5 megabases (Mb) distal to the 8p23 (8p23.1–pter) region, followed by an intermediate intact segment, and then an inverted duplicated proximal segment of approximately 30 MB, from 8p23.1 to 8p11.1 in the first fetus and from 8p23.1 to 8p11.21 in the second. The GATA4 gene has now been implicated in the cardiac defects associated with deletions of 8p23.1. Although both fetuses had VSD, GATA4 was located in the intact region, whereas the NRG1 gene, which is necessary for heart development, was duplicated in our cases. We suggest that duplication of the NRG1 gene could be responsible for the cardiac findings in our cases, but further studies are necessary to confirm this hypothesis.

Partial trisomy 11q is a rare syndrome and may be observed due to an intra-chromosomal duplication or an inter-chromosomal insertion. The deletions of the short arm of chromosome 12 are also uncommon structural aberrations. Only a small fraction of structural chromosome anomalies are related to the unbalanced progeny of balanced translocation carrier parents. We here report on a 10-month-old baby boy who shows a very mild phenotype related to unique chromosomal abnormality, partial trisomy of 11q, and partial monosomy of 12p, due to the maternal balanced reciprocal translocation (11;12). The proband showed a 49.64Mb duplication of 11q14.1-q25 and 0.44Mb deletion of 12p13.33 in chromosomal array analysis. Since it is known that the duplications may cause a milder phenotype than deletions. Dysmorphic facial features, minor cardiac anomalies, respiratory distress, central nervous system anomalies, and psychomotor delay observed in the patient was similar to the reported pure 11q duplication cases, while behavioral problems observed in pure monosomy 12p cases could not be evaluated due to the young age of the patient. Phenotype-genotype correlation will be discussed in view of all the reported pure partial 11q trisomies and pure partial 12p deletion cases. (c) 2014 Wiley Periodicals, Inc.

Isolated partial duplication of the long arm of chromosome 11 is very rare. The main features are dysmorphic facial features, pre/postnatal growth retardation, speech delay, mental retardation, hypotonia, microcephaly, and cardiac, vertebral, limb and genital anomalies. In this case, we report a patient with partial trisomy of 11q13.5 -> qter due to a de novo rearrangement consisting of the whole X chromosome and part of chromosome 11; 46,X,der(X)(Xqter -> Xp22.33::11q13.5 -> 11qter). Additional findings were a separated clavicle, lacrimal duct stenosis and prenatally detected renal hypoplasia. SNP array results revealed a duplication between 11q13.5 and 11qter, measuring 58 Mb, from nucleotide 76,601,607 to 134,926,021. As a result, molecular karyotyping could be performed in such cases in order to establish a definite phenotype-genotype correlation using conventional or molecular cytogenetics techniques. (C) 2013 Elsevier B.V. All rights reserved.

An additional derivative chromosome 8 was found in the cytogenetic analyses of the chorionic villus biopsy specimen of a balanced reciprocal translocation carrier mother. This was a 3:1 segregation of the unbalanced product of the balanced maternal 8:9 translocation. The chromosomes of the carrier of the balanced reciprocal translocation pair with their matching homologous segments at meiosis I, a quadrivalent figure is formed and chromosomes segregate from this configuration. Increased nuchal tranaslucency was also determined on fetal sonography at the 13(rd) week of gestation. The final karyotype was 47,X Y,+der(8)t(8;9)(q11.2;p22) mat, and the parents were informed about this tertiary trisomy. After genetic counseling, the parents decided to terminate the pregnancy. The presented case is a reminder of the probability of the unbalanced products of the 3:1 segregation, rather than the common 2:2 segregation.Dengeli resiprokal translokasyon taşıyıcısı annenin, koryon villüs biyopsi materyalinden yapılan sitogenetik analizinde, ek olarak derivatif 8. kromozom belirlenmiştir. Bu dengesiz durum, 8. ve 9. kromozomlar arasında dengeli resiprokal translokasyon içeren annenin, 3:1 gamet ayrışımından kaynaklanmaktadır. Resiprokal dengeli translokasyon taşıyıcılarının kromozomları, mayoz 1’de homologları ile eşleşebilmek için quadrivalen yapıyı oluşturmakta ve buradan kromozomların segregasyonu sözkonusu olmaktadır. Gebeliğin 13. haftasında yapılan fetal ultrasonografide ayrıca nukkal kalınlık artışı saptanmıştır. Fetüsün karyotipi 47,XY,+der(8)t(8;9)(q11.2;p22) mat olarak rapor edilmiş ve tersiyer trizomi hakkında aileye bilgi verilmiştir. Aile genetik danışmanlık sonrası gebeliğini sonlandırmaya karar vermiştir. Burada sunulan olgu, resiprokal translokasyon taşıyıcılarının dengesiz gamet oluşumunda 2:2 segregasyonun yanısıra, daha az oranda da olsa 3:1 segregasyon olasılığının da olduğunu hatırlatması açısından önemlidir.

Ionizing radiation is a strong physical mutagen, causing breakage of phosphodiester bonds in DNA at any stage of the mitotic cycle. Analysis of sister chromatid exchange (SCE) has come into use as a sensitive DNA-damage indicator. We investigated the SCE rates in radiology technologists who are occupationally and chronically exposed to ionizing radiation. The study included 39 radiology technologists and 35 sex- and age-matched healthy controls. There was a statistically significant difference in the SCE frequency between radiology technologists and controls (p