Hereditary cancer syndromes (HCSs) are a heterogenous group of disorders caused by germline pathogenic variations in various genes that function in cell growth and proliferation. This study aimed to describe the germline variations in patients with hereditary cancer using multigene panels. The molecular and clinical findings of 218 patients with HCS were evaluated. In addition, 25 HCS-related genes were sequenced using a multigene panel, and variations were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria. In total, 218 HCS patients predominantly with breast, colorectal, ovarian, gastric, and endometrium cancers were included. Pathogenic variations in 12 distinct genes were detected in 36 of 218 (16.5%) cases. In this study, the most affected gene was the ATM gene, in which pathogenic variations were detected in 8 of 218 cases, followed by CHEK2 (3.2%), MUTYH (3.2%), BRIP1 (1.8%), BARD1 (0.9%), TP53 (0.9%), PALB2 (0.4%), MLH1 (0.4%), MSH2 (0.4%), PMS2 (0.4%), RAD50 (0.4%), and RAD51C (0.4%). This study contributes to genotype-phenotype correlation in HCSs and expands the variation spectrum by introducing three novel pathogenic variations. The wide spectrum of the gene pathogenic variations detected and the presence of multiple gene defects in the same patient make the multigene panel testing a valuable tool in detecting the hereditary forms of cancer and providing effective genetic counseling and family specific screening strategies.

Introduction: Myhre syndrome (MS; OMIM #139210) is a rare connective tissue disorder presenting with cardiovascular, respiratory, gastrointestinal, and skeletal system findings. Fewer than 100 patients were reported until recently, and all molecularly confirmed cases had de novo heterozygous gain-of-function mutations in the SMAD4 gene. Dysregulation of the TGF-beta signaling pathway leads to axial and appendicular skeleton, connective tissue, cardiovascular system, and central nervous system abnormalities. Case Presentation: Two siblings, 12 and 9 years old, were referred to us because of intellectual disability, neurodevelopmental delay, and dysmorphic facial features. Physical examination revealed hypertelorism, strabismus, small mouth, prognathism, short neck, stiff skin, and brachydactyly. Discussion: With a clinical diagnosis of MS, the SMAD4 gene was analyzed via Sanger sequencing, and a heterozygous c.1486C>T (p.Arg496Cys) pathogenic variation was detected in both of the siblings. The segregation analysis revealed that the mutation was inherited from the father who displayed a milder phenotype. Among the 90 patients in the literature, one family was reported in which two siblings carried the same variation (p.Arg496Cys), inherited from the severely affected mother. We are reporting the second family which has three affected family members, a father and two children. We report this study to remind the clinicians to be aware of the parental transmission of SMAD4 variations and also evaluate the parents of the Myhre cases.

Background: Familial adenomatous polyposis (OMIM #175100) and MUTYH-associated polyposis (OMIM #608456) are rare cancerprone disorders characterized by hundreds of adenomatous polyps in the colon and rectum, which have a high probability of malignant transformation. Attenuated familial adenomatous polyposis is a variant of familial adenomatous polyposis, which is a term used for the condition in which patients have less than 100 colorectal polyps. Germline heterozygous Adenomatous polyposis coli (APC) and biallelic MUTYH (mutY DNA glycosylase) pathogenic variations are responsible for familial adenomatous polyposis and MUTYH-associated polyposis respectively. The aim of this study is to discuss the clinical manifestations of patients having pathogenic APC and MUTYH variations. Methods: We included 27 probands who have more than 10 colonic polyps in this study. After evaluation of their clinical and family histories, the probands were screened for APC and MUTYH variations via next generation sequencing. The family members of the probands carrying pathogenic variations were screened via Sanger sequencing. Results: Among 27 probands, pathogenic APC and MUTYH variations were detected in 3 and 6 probands respectively. In the APC gene, 3 novel truncating variations (p.Leu360*, p.Leu1489Phefs*23, and p.Leu912*) were detected in 3 unrelated probands. In the MUTYH gene, only 2 distinct pathogenic variations were detected (p.Pro295Leu and p.Glu480del) in the homozygous or compound heterozygous state. Conclusion: In this study, molecular etiology was clarified in 9 familial polyposis patients. The p.Pro295Leu and p.Glu480del variations seem to be common in the Turkish population and may be considered as a first-step genetic test in Turkish familial polyposis patients showing autosomal recessive inheritance. However more studies are needed to reveal the exact frequency of these variations.

Background. Biotin is a water-soluble vitamin that plays a key role in carboxylation. The formation of free biotin is impaired in biotinidase deficiency (BD), resulting in impaired biotin-dependent carboxylase functions. Based on the percentage of residual serum enzyme activity, BD is classified as partial and profound. Methods. Retrospective data including gender, age, parental consanguinity, family history, biotinidase activity analyses, type of deficiency (partial-profound), physical examination, treatment, and genotypes were evaluated in patients diagnosed with biotinidase deficiency in a single center in the eastern region of Türkiye. Patients whose biotinidase enzyme activity was below 30% with biallelic variants in the BTD gene were diagnosed as BD. Results. A total of 302 patients were included in the study. Parental consanguinity was present in 135 (44.7%) of them. Two hundred eighty-six (94.7%) were diagnosed by neonatal screening, 14 (4.6%) by family screening and two (0.06%) by clinical symptoms. Ninety-two (30.5%) of the patients were followed-up with profound deficiency and 210 (69.5%) with partial deficiency. A total of 306 variants were detected. Twenty different variants (3 novel - 3 rare) and 31 different genotypes were detected. The 3 most frequently detected variants were c.410G>A (p.Arg137His; 47.3%), c.1270G>C (p.Asp424His; 29.7%), and c.38_44delGCGGCTGinsTCC (p.Cys13Phefs*36; 15.3%). The 3 most frequently identified genotypes were c.410G>A (p.Arg137His) / c.1270G>C (p.Asp424His) compound heterozygous (32.4%), c.410G>A (p.Arg137His) homozygous (24.8%), and c.38_44delGCGGCTGinsTCC (p.Cys13Phefs*36) / c.1270G>C (p.Asp424His) compound heterozygous (12.2%). Patients with c.410G>A (p.Arg137His) homozygous variant, c.38_44delGCGGCTGinsTCC (p.Cys13Phefs*36) homozygous variant and c.38_44delGCGGCTGinsTCC (p.Cys13Phefs*36) / c.410G>A (p.Arg137His) compound heterozygous variant were statistically significantly associated with profound deficiency. Compound heterozygosity of c.410G>A (p.Arg137His) / c.1270G>C (p.Asp424His) variants were significantly associated with partial deficiency. Conclusions. The association between the BTD genotype and biochemical phenotype is not always consistent. Our study provides valuable data by adding variants with genotype-phenotype correlations to the literature and three novel variants, which can provide significant guidance in clinical follow-up.

Context: Hereditary hypophosphatemia (HH), is a rare condition related to decreased renal tubular phosphate reabsorption. Although X-linked hypophosphatemia or PHEX gene variant is the most frequent cause of HH, recent advances in next-generation sequencing (NGS) techniques enable the identification of genetic etiologies as a whole. Objective: This work aimed to identify genetic causes of HH using various genetic testing methods and to compare clinical features between FGF23-dependent and FGF23-independent HH groups. Methods: Fifty patients (24 males) from 39 unrelated families were included. Based on initial evaluation, PHEX gene sequencing was performed in patients with clinical and biochemical findings suggestive of FGF23-dependent HH. If sequencing showed no alterations, multiplex ligation-dependent probe amplification (MLPA) analysis for PHEX was conducted. Initially, a specific gene panel was performed for FGF23-independent HH or those in whom the PHEX gene showed no genetic alteration. Results: Genetic etiology was revealed in 43 patients from 33 families. PHEX gene variants (4 novel) were identified in 24 patients from 19 unrelated families (50%). SLC34A3 was the second most common (16.6%) and the rest were rarer causes of hypophosphatemia (DMP1 n = 3, SLC34A1 n = 2, CLCN5 n = 2, OCRL n = 2, FAM20C n = 1, SLC2A2 n = 1). When the genetically proven FGF23-dependent (n = 28) and FGF23-independent (n = 15) HH groups were compared for clinical and biochemical features; lower phosphate and TmP/GFR SDSs and higher ALP SDS with more severe clinical rickets were detected in FGF23-dependent group, whereas higher serum and urine calcium and lower PTH levels were detected in FGF23-independent group. Conclusion: The application of MLPA provided an additional explanatory value of 10% to the molecular etiology. However, 10% of the cases of HH still remain unexplained even after a comprehensive genetic work-up. Biochemical findings suggest distinct biochemical profiles between FGF23-dependent and FGF23-independent HH groups.