Genetic heterogeneity, reduced penetrance, and variable expressivity, the latter including asymmetric body axis plane presentations, have all been described in families with congenital limb ...malformations (CLMs). Interfamilial and intrafamilial heterogeneity highlight the complexity of the underlying genetic pathogenesis of these developmental anomalies. Family-based genomics by exome sequencing (ES) and rare variant analyses combined with whole-genome array-based comparative genomic hybridization were implemented to investigate 18 families with limb birth defects. Eleven of 18 (61%) families revealed explanatory variants, including 7 single-nucleotide variant alleles and 3 copy number variants (CNVs), at previously reported “disease trait associated loci”: BHLHA9, GLI3, HOXD cluster, HOXD13, NPR2, and WNT10B. Breakpoint junction analyses for all three CNV alleles revealed mutational signatures consistent with microhomology-mediated break-induced replication, a mechanism facilitated by Alu/Alu-mediated rearrangement. Homozygous duplication of BHLHA9 was observed in one Turkish kindred and represents a novel contributory genetic mechanism to Gollop-Wolfgang Complex (MIM: 228250), where triplication of the locus has been reported in one family from Japan (i.e., 4n = 2n + 2n versus 4n = 3n + 1n allelic configurations). Genes acting on limb patterning are sensitive to a gene dosage effect and are often associated with an allelic series. We extend an allele-specific gene dosage model to potentially assist, in an adjuvant way, interpretations of interconnections among an allelic series, clinical severity, and reduced penetrance of the BHLHA9-related CLM spectrum.
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Duan et al. implemented family-based genomics and rare variant analyses in 18 families with CLMs. The results show that allelic series and gene dosage effects contribute to the clinical variability . The allele-specific gene dosage model (AsGD) explains observations of the BHLHA9-related clinical spectrum including the Gollop-Wolfgang complex (MIM: 228250).
Cystic fibrosis (CF) is the most common worldwide, life-shortening multisystem hereditary disease, with an autosomal recessive inheritance pattern caused by mutations in the cystic fibrosis ...transmembrane conductance regulator (
) gene. The national newborn screening (NBS) program for CF has been initiated in Turkey since 2015. If the immunoreactive trypsinogen (IRT) is elevated (higher than 70 μg/L in the second control) and confirmed by sweat test or clinical findings, genetic testing is performed. The aims of this study are to emphasize the effect of NBS on the status of genetic diagnosis centers with the increasing numbers of molecular testing methods, and to determine the numbers and types of
mutations in Turkey.
The next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) results of 1595 newborns, who were referred to Cukurova University Adana Genetic Diseases Diagnosis and Treatment Center (AGENTEM) for molecular genetic testing, were evaluated with positive CF NBS program results since 2017.
According to the results; 560 (35.1%) of the 1595 patients carried at least 1 (one) CF-related variant, while 1035 patients (64.9%) had no mutation. Compound heterozygosity for two mutations was the most common in patients, while two detected variants were homozygote in 14 patients. A total of 161 variants were detected in 561 patients with mutations. Fifteen novel variants that have not been previously reported were found. Moreover, p.L997F was identified as the most frequent pathogenic mutation that might affect the IRT measurements used for the NBS. The distribution of mutation frequencies in our study showed a difference from those previously reported; for example, the well-known p.F508del was the third most common (
= 42 alleles), rather than the first. The most striking finding is that 313 cases had a pathogenic variant together with the V470M variant, which might have a cumulative effect on CF perpetuation.
This study is the first to determine the mutational spectrum of CFTR in correlation with the NBS program in the Turkish population. NBS for CF raises issues regarding screening in diverse populations, both medical and non-medical benefits, and carrier identification. Through the lens of NBS, we focused on the integrated diagnostic algorithms and their effect on the results of genetic testing.
BRCA1/2 mutations play a significant role in cancer pathogenesis and predisposition particularly in breast, ovarian and prostate cancers. Thus, germline analysis of BRCA1 and BRCA2 is essential for ...clinical management strategies aiming at the identification of recurrent and novel mutations that could be used as a first screening approach. We analyzed germline variants of BRCA1/2 genes for 2168 individuals who had cancer diagnosis or high risk assessment due to BRCAs related cancers, referred to 10 health care centers distributed across 7 regions covering the Turkish landscape. Overall, 68 and 157 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-two novel variants were reported from both genes while BRCA2 showed higher mutational heterogeneity. We herein report the collective data as BRCA Turkish consortium that confirm the molecular heterogeneity in BRCAs among Turkish population, and also as the first study presenting the both geographical, demographical and gene based landscape of all recurrent and novel mutations which some might be a founder effect in comparison to global databases. This wider perspective leads to the most accurate variant interpretations which pave the way for the more precise and efficient management affecting the clinical and molecular aspects.
•A similar percentage of clinically unaffected individuals were also identified with potentially pathogenic variants.•Based on the geographic examinations, Eastern Anatolian and the Mediterranean region had the lowest positivity rates.•The Southeastern Anatolian region showed the lowest density of both patients and clinically relevant genetic changes.
Mucolipidosis type‐II (ML‐II) is an ultra‐rare disorder caused by deficiency of N‐acetylglucosaminyl‐1‐phosphotransferase enzyme due to biallelic pathogenic variants in GNPTAB gene. There are a few ...known about the natural history of ML‐II. In this study, we presented the natural course of 24 patients diagnosed with ML‐II. Mean age at diagnosis was 9.3 ± 5.7 months. All patients had coarse face, developmental delay, and hypotonia. The mean survival time was 3.01 ± 1.4 years. The oldest patient was 6.5 years old. Twelve patients died due to lung infection and respiratory failure. We observed early and significant radiological findings of ML‐II were different from typical dysostosis multiplex such as femoral cloaking, rickets‐like changes, and talocalcaneal stippling. These are significant findings observed in the fetal or newborn period which is considered to be highly characteristic of ML‐II and disappears in the first year. Cloaking, rickets‐like changes, and stippling were not observed in patients older than three months of age and this suggests that these findings disappear within the first year. These radiological features can be used as important clues for diagnosis. We detected eight different pathogenic variants in GNPTAB gene, three of them were novel.
Severe congenital neutropenia (SCN) is a rare disease. Autosomal recessive forms of SCN are more frequent in countries where consanguineous marriages are common. In this report, we describe a ...54-day-old female with neutropenia who presented with ecthyma gangrenosum. Clinical exome sequencing was used to identify the mutation. HAX1 messenger RNA and isoforms were examined by real-time quantitative and conventional polymerase chain reaction. Bone marrow aspiration was stained by hematoxylin and eosin. Granulocytes were tested for apoptosis upon H2O2 exposure. T-cell proliferation was tested by flow cytometry. Clinical exome sequencing revealed a novel homozygous acceptor splice site mutation in intron 3 of HAX1 (c.505-1G>C), which reduced both isoforms A and B of HAX1 messenger RNA. The Western blot studies showed a complete absence of HAX1 protein. The purified neutrophils from the patient showed increased apoptosis upon H2O2 exposure, whereas T-cell proliferative responses to various stimuli were intact. The patient was treated with combined antibiotics, filgrastim, and placed on antibiotics prophylaxis. To the best of our knowledge, our data provide the first experimental evidence for HAX1 deficiency because of a splice site mutation. Although 3 other splice site variants have been deposited in databases, functional studies were missing. This novel variant of HAX1 may explain the SCN and secondary infections in our patients.
Abstract
Pontocerebellar hypoplasia (PCH) constitutes a heterogeneous neurodegenerative/neurodevelopmental disorder of the pons and cerebellum with onset in the prenatal period. Our study aimed to ...present different clinical and radiological manifestations of our genetically diagnosed PCH patients.
Method:
Six patients were enrolled in this study from September 2018 to March 2021. All the clinical radiological and genetic investigations were done at Cukurova University Medical School.
Results:
Five children were diagnosed genetically and categorized under one of the types of PCH (type 10,7,11). Homozygous mutations in
CLP1
In PCH type 10,
TOE1
in PCH type 7, and
TBC1D2
3 in PCH type 11 were respectively detected. Pateint with PCH type 11 and female patient with PCH type 7 could walk and speak few words. Male patient with PCH type 7 had disorder of sex development.
Conclusion:
According to our study, PCH is a rare neurodegenerative disease, although some types are static as PCH11 male gender and PCH7 female gender. Some clinical features are specific to a definite type. PCH7 express disorders of sex development most apparent in 46 XY. Some ethnic groups could express distinct subtypes. PCH10 is seen in the Turkish population. Radiological imaging is beneficial in pre-diagnosis; all the patients had different pons and cerebellar hypoplasia degrees. Genetic testing like whole exome sequencing -next-generation sequencing is essential in setting the definite diagnosis and determining the type/subtype of PCH.
Objective: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in social skills and communication with repetitive behaviors. Etiology is still unclear although ...it is thought to develop with interaction of genes and environmental factors. Oxytocin has extensive effects on intrauterine brain development. Vitamin D, affects neural development and differentiation and contributes to the regulation of around 900 genes including oxytocin receptor gene. In the present study, the contribution of D vitamin receptor and oxytocin receptor gene polymorphisms in the development of ASD in Turkish community was investigated. To our knowledge, this is the first study examining these two associated genes together in the literature.
Methods: Eighty-five patients diagnosed with ASD according to DSM-5 who were referred to outpatient clinics of Child and Adolescent Psychiatry of Başkent University and Mersin University and 52 healthy, age and gender-matched controls were included in the present study. Vitamin D receptor gene rs731236 (Taq1), rs2228570 (Fok1), rs1544410 (Bsm1), rs7975232 (Apa1) polymorphisms and oxytocin receptor gene rs1042778 and rs2268493 polymorphisms were investigated using real time polymerase chain reaction method.
Results: No significant difference between groups in terms of distribution of genotype and alleles in each of polymorphisms for these genes could be found.
Conclusion: Knowledge of genes and polymorphisms associated with the development of ASD may be beneficial for early diagnosis and future treatment. Further studies with larger populations are required to demonstrate molecular pathways which may play part in the development of ASD in Turkey. KCI Citation Count: 2
Cases of neurofibromatosis type 1 (
)-associated medullary thyroid carcinoma (MTC) or C-cell hyperplasia are rarely associated with other endocrine tumors or cases with a multiple endocrine neoplasia ...type 2. In these patients, mutations were detected in the
gene but no mutations were detected in the
gene. Although vandetanib has been shown to improve progression-free survival in adults with advanced MTC, data in pediatric patients are limited. Herein, we report the use and outcome of vandetanib in a pediatric MTC case in which
gene and
proto-oncogen mutation were identified together.
Breast cancer (BC) is the most common cancer type in women and may be inherited, mostly in an autosomal dominant pattern. The clinical diagnosis of BC relies on the published diagnostic criteria, and ...analysis of two genes,
and
, which are strongly associated with BC, are included in these criteria. The aim of this study was to compare BC index cases with non-BC individuals in terms of genotype and diagnostic features to investigate the genotype/demographic information association.
Mutational analyses for the
genes was performed in 2475 individuals between 2013-2022 from collaborative centers across Turkey, of whom 1444 with BC were designated as index cases.
Overall, mutations were identified in 17% (421/2475), while the percentage of mutation carriers in cases of BC was similar, 16.6% (239/1444).
gene mutations were detected in 17.8% (131/737) of familial cases and 12% (78/549) of sporadic cases. Mutations in
were found in 4.9%, whereas 12% were in
(p<0.05). Meta-analyses were performed to compare these results with other studies of Mediterranean-region populations.
Patients with
mutations were significantly more common than those with
mutations. In sporadic cases, there was a lower proportion with
variants, as expected, and these results were consistent with the data of Mediterranean-region populations. However, the present study, because of the large sample size, revealed more robust findings than previous studies. These findings may be helpful in facilitating the clinical management of BC for both familial and non-familial cases.
Infertility is a disease of the male or female reproductive system and is defined as the inability to achieve pregnancy after 12 months or more of regular and unprotected sexual intercourse. Data ...shows that more than 186 million people worldwide are infertile. About 10% of the women of reproductive age are unable to conceive or maintain a pregnancy. In this study, the causes of female infertility were reviewed under several headings and the importance of genetic counseling in infertility was also mentioned. There are many different causes of female infertility, including both genetic and non-genetic causes. In this review, current developments and approaches in the genetic etiology of female infertility were reviewed under six main headings, chromosomal abnormalities, female genital system disorders, hypogonadotropic hypogonadism, primary ovarian failure, polycystic ovary syndrome, and gonadal dysgenesis. Also, the role of genetic counseling in these diseases was discussed. The aim of genetic counseling is to inform people with a hereditary disease or at high risk of carrying it about the course of the disease and treatment methods, and also to guide future generations and family members about their risks. After all tests and examinations, genetic counseling has a very important place in reproductive health.
İnfertilite, erkek veya kadın üreme sisteminin bir hastalığı olup, 12 ay veya daha uzun süre düzenli ve korunmasız cinsel ilişkiden sonra gebelik elde edilememesi olarak tanımlanır. Veriler, dünya çapında 186 milyondan fazla insanın infertil olduğunu göstermektedir. Üreme çağındaki kadınların yaklaşık %10'u gebe kalamaz veya hamileliğini sürdüremez. Bu çalışmada kadın infertilitesinin nedenleri çeşitli başlıklar altında incelenmiş ve ayrıca infertilitede genetik danışmanlığın önemine de değinilmiştir. Kadın infertilitesinin hem genetik ve hem de genetik olmayan nedenler de dahil olmak üzere birçok farklı nedeni vardır. Bu derlemede kadın infertilitesinin genetik etiyolojisindeki güncel gelişmeler ve yaklaşımlar, kromozom anomalileri, kadın genital sistem bozuklukları, hipogonadotropik hipogonadizm, primer over yetmezliği, polikistik over sendromu ve gonadal disgenezi olmak üzere altı ana başlık altında incelenmiştir. Ayrıca bu hastalıklarda genetik danışmanlığın rolü de tartışılmıştır. Genetik danışmanlığın amacı, kalıtsal bir hastalığı olan veya taşıyıcı olma riski yüksek olan kişileri hastalığın seyri ve tedavi yöntemleri hakkında bilgilendirmek, aynı zamanda gelecek nesillere ve aile bireylerine de riskleri konusunda rehberlik etmektir. Tüm test ve tetkiklerden sonra, üreme sağlığında genetik danışmanlık çok önemli bir yere sahiptir.
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