Objective: Turkish genome is underrepresented in large genomic databases. This study aims to evaluate the effect of allele frequency in the Turkish population in determining the clinical utility of germline findings in breast cancer, including invasive lobular carcinoma (ILC), mixed invasive ductal and lobular carcinoma (IDC‐L), and ductal carcinoma (DC).Methods: Two clinic‐based cohorts from the Umraniye Research and Training Hospital (URTH) were used in this study: a cohort consisting of 132 women with breast cancer and a non‐cancer cohort consisting of 492 participants. The evaluation of the germline landscape was performed by analysis of 27 cancer genes. The frequency and type of variants in the breast cancer cohort were compared to those in the non‐cancer cohort to investigate the effect of population genetics. The variant allele frequencies in Turkish Variome and gnomAD were statistically evaluated.Results: The genetic analysis identified 121 variants in the breast cancer cohort (actionable = 32, VUS = 89) and 223 variants in the non‐cancer cohort (actionable = 25, VUS = 188). The occurrence of 21 variants in both suggested a possible genetic population effect. Evaluation of allele frequency of 121 variants from the breast cancer cohort showed 22% had a significantly higher value in Turkish Variome compared to gnomAD (p < 0.0001, 95% CI) with a mean difference of 60 times (ranging from 1.37–354.4). After adjusting for variant allele frequency using the ancestry‐appropriate database, 6.7% (5/75) of VUS was reclassified to likely benign.Conclusion: To our knowledge, this is the first study of population genetic effects in breast cancer subtypes in Turkish women. Our findings underscore the need for a large genomic database representing Turkish population‐specific variants. It further highlights the significance of the ancestry‐appropriate population database for accurate variant assessment in clinical settings.

Women with germline pathogenic variants (PV) in the fumarate hydratase (FH) gene develop cutaneous and uterine leiomyomata and have an increased risk of developing aggressive renal cell carcinomas. Many of these women are unaware of their cancer predisposition until an atypical uterine leiomyoma is diagnosed during a myomectomy or hysterectomy, making a streamlined genetic counseling process after a pathology-based atypical uterine leiomyoma diagnosis critical. However, the prevalence of germline pathogenic/likely PVs in FH among atypical uterine leiomyomata cases is unknown. To better understand FH germline PV prevalence and current patterns of genetic counseling and germline genetic testing, we undertook a retrospective review of atypical uterine leiomyomata cases at a single large center. We compared clinical characteristics between the FH PV, FH wild-type (WT), and unknown genetic testing cohorts. Of the 144 cases with atypical uterine leiomyomata with evaluable clinical data, only 49 (34%) had documented genetic test results, and 12 (8.3%) had a germline FH PV. There were 48 IHC-defined FH-deficient cases, of which 41 (85%) had FH testing and nine had a germline FH PV, representing 22% of the tested cohort and 18.8% of the FH-deficient cohort. Germline FH PVs were present in 8.3% of evaluable patients, representing 24.5% of the cohort that completed genetic testing. These data highlight the disconnect between pathology and genetic counseling, and help to refine risk estimates that can be used when counseling patients with atypical uterine leiomyomata. Prevention Relevance: Women diagnosed with fumarate hydratase (FH)-deficient uterine leiomyomata are at increased risk of renal cancer. This work suggests a more standardized pathology-genetic counseling referral pathway for these patients, and that research on underlying causes of FH-deficient uterine leiomyomata in the absence of germline FH pathogenic/likely pathogenic variants is needed.

Novel de Novo Nonsense Variants in AGO3 and KHSRP: Insights into Global Developmental Delay and Autism Spectrum Disorders through Whole Genome Analysis - Article abstract #943641

Purpose: An investigation for the co-occurrence of two unrelated genetic disorders of muscular dystrophy and Prader-Willi syndrome (PWS) (OMIM#176270) using joint whole genome sequencing (WGS). Methods: Trio WGS joint analysis was performed to investigate the genetic etiology in a proband with PWS, prolonged muscular hypotonia associated hyperCKemia, and early-onset obesity. The parents were unaffected. Results: Results showed maternal isodisomy uniparental disomy (UPD) in chromosome 15, expanding from 15q11.2 to 15q22.2, including PWS regions at 15q11.2–15q13. Maternal heterodisomy was detected from 15q22.2 to 15q26.3. A pathogenic variant, NM_000070.3(CAPN3):c.550del (p.Thr184fs), was identified at 15q15.1 in a heterozygous state in the mother that was homozygous in the proband due to maternal isodisomy. Conclusion: This is the first study of the concurrent molecular etiology of PWS and calpainopathy (OMIM#253600) in the same patient. This report highlights the utility of joint analysis and the need for the assessment of autosomal recessive disease in regions of isodisomy in patients with complex and unexplained phenotypes.

Background: Intellectual developmental disorder with autism and speech delay (IDDAS) is a rare and complex neurological disorder characterized by the presence of both intellectual and speech impairment and features of autism spectrum disorder (ASD). The prevalence of IDDAS is unknown but genetically, it is caused by heterozygous variants in the TBR1 gene. Methods: A 7-year-old female with autistic features and delayed speech development was presented with unaffected parents. Trio-joint analysis was conducted on whole-genome sequencing (WGS) data from the proband and unaffected parents. A phenotype-driven analysis was conducted to investigate variants related to the patient’s clinical presentation. A zygosity-focused analysis was performed to investigate de novo and compound heterozygote variants related to the etiology. Results: The joint-genome analysis identified a novel NM_006593.4(TBR1):c.1303C>T p.Gln435* nonsense variant in the proband. The de novo analysis confirmed the absence of the variant in the parents. No additional causative variants were identified in genes associated with the proband’s phenotype. Conclusions: This is the first report of the NM_006593.4(TBR1):c.1303C>T variant in a patient with IDDAS. This study presents the clinical features of the patient and highlights details of trio-WGS analysis in the molecular diagnosis of this complex disease. Sharing these details is important, as they contribute to the understanding of the spectrum of this rare syndrome.

Purpose: Investigation for the co-occurrence of two unrelated genetic disorders of muscular dystrophy and Prader-Willi syndrome (PWS) (OMIM # 176270) using joint whole genome sequencing (WGS). Methods: Trio WGS joint analysis was performed to investigate the genetic etiology in a proband with PWS, prolonged muscular hypotonia associated hyperCKemia, and early-onset obesity. The parents were unaffected. Results: Results showed maternal isodisomy uniparental disomy (UPD) in chromosome 15 expanding from 15q11.2 to 15q22.2, including PWS regions at 15q11.2-15q13. Maternal heterodisomy was detected from 15q22.2 to 15q26.3. A pathogenic variant, NM_000070.3(CAPN3):c.550del (p.Thr184fs), was identified at 15q15.1 in a heterozygous state in the mother that was homozygous in the proband due to maternal isodisomy. Conclusion: This is the first study of the concurrent molecular etiology of PWS and calpainopathy (OMIM # 253600) in the same patient. This report highlights the utility of joint analysis and need for the assessment of autosomal recessive disease in regions of isodisomy in patients with complex and unexplained phenotype.