Frequency and distribution of BRCA1/BRCA2 large genomic rearrangements in Turkish population with breast cancer.

Germline mutations in BRCA1 and BRCA2 genes are mainly responsible for breast and/or ovarian cancer patients. Most of the mutations in these genes are single nucleotide changes or deletions/insertions of small numbers of bases, while a minority of mutations in these genes are large genomic rearrangements (LGRs). The frequency of LGRs in the Turkish population is not clearly known. Also insufficient awareness of the importance of LGRs in breast and/or ovarian cancer development can lead to some disruptions in patient management. So, we aimed to determine the frequency and distribution of the LGRs in the BRCA1/2 genes in the Turkish population. We investigated rearrangements of BRCA genes using multiplex ligation-dependent probe amplification (MLPA) analysis in 1540 patients with a personal and/or family history of breast and/or ovarian cancer or who had familial known large deletion/duplication and applied for segregation. The estimated overall frequency of LGRs in our group was 3,4% (52/1540) with 91% in BRCA1 gene and 9% in BRCA2 gene. 13 different rearrangements were detected (10 BRCA1, 3 BRCA2). To the best our knowledge, BRCA1 exon 1-16 duplication and BRCA2 exon 6 deletion have not been previously reported before. Our study results supported that the detection of rearrangements in BRCA genes is of great importance and it should be planned routinely in patients whose mutations cannot be detected by sequence analysis in screening programs.

Clinical and molecular genetic findings of Crisponi/cold-induced sweating syndrome (CS/CISS) spectrum in patients from Turkey.

Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by episodic hyperthermia, arthrogryposis, impaired feeding ability, and respiratory distress. The classic CS/CISS is mainly associated with CRLF1 and, rarely, CLCF1. PERCHING syndrome, previously known as CS/CISS type-3 associated with biallelic pathogenic variants in KLHL7, is notable for its few overlapping manifestations. This study presents genotype-phenotype relationships in CS/CISS-like spectrum associated with CRLF1 and KLHL7. Clinical findings of 19 patients from 14 families and four patients from three families were found in association with six different CRLF1 and three different KLHL7 variants, respectively. c.167T>C and c.713delC of the CRLF1 gene and the c.642G>C of the KLHL7 were novel. The c.708_709delCCinsT allele of CRLF1 was identified in 10 families from the Mardin province of Turkey, underlining that an ancestral haplotype has become widespread. CRLF1-associated phenotypes revealed novel manifestations such as prenatal oligohydramnios, benign external hydrocephalus, previously unreported dysmorphic features emerging with advancing age, severe palmoplantar keratoderma and facial erythema, hypopigmented macules and streaks, and recurrent cardiac arrests. KLHL7 variants presented with glabellar nevus flammeus, blepharophimosis, microcephaly, thin corpus callosum, and cleft palate. Abnormalities of sweating, observed in one patient reported herein, is known to be very rare among KLHL7-related phenotypes.

An update of the mutation spectrum of phenylalanine hydroxylase (PAH) gene in the population of Turkey.

Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine metabolism, mostly caused by PAH gene variants. The aim of this study was to identify the frequency of PAH gene variants in Turkish population with PKU. In 433 patients with PKU, PAH gene was examined using next generation sequencing (NGS) method. IVS10- 11G>A, p.R261Q, p.A300S, p.A403V, and p.T380 variants, which are the most common variants in this study, constituted 45,9% of the variants in our study. Nine novel variants p.A34V, K73Qfs*4, R157H, R261S, p.T266I, p.S310P, T328A, p.F351I, and K363N were identified. This study determines the most common PAH variants in Turkey and shows that PKU can be screened before marriage with the screening kits. Identification of the PAH gene variant spectrum is important for early diagnosis, understanding molecular mechanisms, clinical follow-up, treatment, and genetic counseling. And the novel variants found this study are important for further studies.

How to Manage Low Estriol Levels in Pregnancies, One Center Experience.

Objective: Low estriol (uE3) levels in the second-trimester screening for Down syndrome may be the result of fetal demise, congenital abnormalities, or some genetic hormonal disorders of the fetus. Although X-linked ichthyosis, a microdeletion syndrome with mild ichthyosis, which causes steroid sulfatase (STS) deficiency, is the most common genetic cause, second-trimester screening tests calculate the risk for a less common and severe disorder known as the Smith Lemli Opitz syndrome (SLOS). We aimed to investigate the outcomes of pregnancies with low uE3 levels in Down syndrome screening and emphasize the high prevalence of STS deficiency instead of SLOS in such cases. Methods: Fifteen pregnancies with very low uE3 levels and high risk for trisomy and/or SLOS in screening tests were evaluated and tested for STS deficiency and SLOS. Results: Seven of the pregnancies had STS microdeletion syndrome, while additional two cases were supposed to have STS gene mutation according to family and/or postnatal history. Although one fetal death was recorded, no chromosomal abnormality, SLOS, or congenital malformation was recorded in our series. Conclusions: SLOS is a very severe and rare syndrome. The risk estimation for SLOS in screening tests causes stress for pregnant women and healthcare givers. We recommend the addition of risk estimation for STS deficiency when a low uE3 level is detected in the screening test.

Intelligent Ratio: A New Method for Carrier and Newborn Screening in Spinal Muscular Atrophy.

Aim: Spinal muscular atrophy (SMA) is an inherited, autosomal recessive neuromuscular disease that causes high morbidity and mortality. The prevalence is 1-2/100,000, while the incidence is 1/6000-1/10,000 among live births. Due to the high carrier frequency (1/40-1/60) of SMA-associated alleles, screening can prevent new cases. The aim of the current study was to present the development of a new, quantitative, real-time, polymerase chain reaction (PCR)-based screening test that uses an intelligent ratio (IR) for analyses, as well as a comparison of the results with the gold standard. Materials and Methods: Included in the study were 100 patients with various risk genotypes for survivor motor neuron 1 (SMN1) and SMN2 genes whose genetics had been previously investigated using multiplex ligation probe amplification (MLPA). A combination of the 5' nuclease assay and allele-specific PCR was used to quantify the SMN1 deletion mutation with real-time PCR using the FII gene as a reference. All of the optimized standards were adapted to software that provided automated analyses. The approval number of the institutional ethics committee for the study is 2012-KAEK-15/1497. Results: The results of the screening test were completely compatible with the MLPA results; it achieved 100% sensitivity and specificity compared with the gold standard. The use of the IR in the analyses provided a user-independent method that quickly and accurately provided results, regardless of the amount of DNA used of the extraction method. Conclusion: Carrier or newborn screening of SMA is essential in countries that have high rates of consanguineous marriages. The screening test presented in this study that uses FII as a reference gene proved to be low-cost, reliable, applicable, accurate, and amenable to use in an automated system for SMA screening.