Rare germline variants in individuals diagnosed with schizophrenia within multiplex families

Backgrounds and Objective: Blue rubber bleb nevus syndrome (BRBN) or Bean syndrome is a rare Venous Malformation (VM)-associated disorder, which mostly affects the skin and gastrointestinal tract in early childhood. Somatic mutations in TEK have been identified from BRBN patients; however, the etiology of TEK mutation-negative patients of BRBN need further investigation. Method: Two unrelated sporadic BRBNs and one sporadic VM were firstly screened for any rare nonsilent mutation in TEK by Sanger sequencing and subsequently applied to whole-exome sequencing to identify underlying disease causative variants. Overexpression assay and immunoblotting were used to evaluate the functional effect of the candidate disease causative variants. Results: In the VM case, we identified the known causative somatic mutation in the TEK gene c.2740C>T (p.Leu914Phe). In the BRBN patients, we identified two rare germline variants in GLMN gene c.761C>G (p.Pro254Arg) and c.1630G>T(p.Glu544*). The GLMN-P254R-expressing and GLMN-E544X-expressing HUVECs exhibited increased phosphorylation of mTOR-Ser-2448 in comparison with GLMN-WTexpressing HUVECs in vitro. Conclusion: Our results demonstrated that rare germline variants in GLMN might contribute to the pathogenesis of BRBN. Moreover, abnormal mTOR signaling might be the pathogenesis mechanism underlying the dysfunction of GLMN protein.

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Germline EGFR variants are over-represented in adolescents and young adults (AYA) with adrenocortical carcinoma

Human Molecular Genetics ◽

10.1093/hmg/ddaa268 ◽

2020 ◽

Author(s):

Sara Akhavanfard ◽

Lamis Yehia ◽

Roshan Padmanabhan ◽

Jordan P Reynolds ◽

Ying Ni ◽

...

Keyword(s):

Young Adults ◽

Adrenocortical Carcinoma ◽

Kinase Inhibitor ◽

Mapk Pathway ◽

Adolescents And Young Adults ◽

Control Group ◽

Precision Oncology ◽

Sequencing Data ◽

Germline Variants ◽

Mutant Cells

Abstract Adrenocortical Carcinoma (ACC) is a rare endocrine tumor with poor overall prognosis and 1.5-fold overrepresentation in females. In children, ACC is associated with inherited cancer syndromes with 50–80% of childhood-ACC associated with TP53 germline variants. ACC in adolescents and young adults (AYA) is rarely due to germline TP53, IGF2, PRKAR1A and MEN1 variants. We analyzed exome sequencing data from 21 children (<15y), 32 AYA (15-39y), and 60 adults (>39y) with ACC, and retained all pathogenic, likely pathogenic, and highly prioritized variants of uncertain significance. We engineered a stable lentiviral-mutant ACC cell line, harboring an EGFR variant (p.Asp1080Asn) from a 21-year-old female without germline-TP53-variant and with aggressive ACC. We found that 4.8% of the children (P = 0.004) and 6.2% of AYA (P < 0.0001), all-female participants, harbored germline EGFR variants, compared to only 0.3% of the control group. Expanding our analysis to the RTK-RAS-MAPK pathway, we found that the RTK genes have the highest number of highly prioritized germline variants in these individuals amongst all three arms of this pathway. We showed EGFR mutant cells migrate faster and are characterized by a stem-like phenotype compared to wild type cells. While EGFR inhibitors did not affect the stemness of mutant cells, Sunitinib, a multireceptor tyrosine kinase inhibitor, significantly reduced their stem-like behavior. Our data suggest that EGFR could be a novel underlying germline predisposition factor for ACC, especially in the Childhood-AYA (C-AYA) population. Further clinical validation can improve precision oncology management of this disease, which is known to have limited therapeutic options.

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Hunting for Familial Parkinson’s Disease Mutations in the Post Genome Era

Genes ◽

10.3390/genes12030430 ◽

2021 ◽

Vol 12 (3) ◽

pp. 430

Author(s):

Steven R. Bentley ◽

Ilaria Guella ◽

Holly E. Sherman ◽

Hannah M. Neuendorf ◽

Alex M. Sykes ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Family History ◽

Rare Variants ◽

Strong Family History ◽

Disease Mutations ◽

Whole Exome ◽

History Of ◽

Functional Consequences ◽

Multiplex Families

Parkinson’s disease (PD) is typically sporadic; however, multi-incident families provide a powerful platform to discover novel genetic forms of disease. Their identification supports deciphering molecular processes leading to disease and may inform of new therapeutic targets. The LRRK2 p.G2019S mutation causes PD in 42.5–68% of carriers by the age of 80 years. We hypothesise similarly intermediately penetrant mutations may present in multi-incident families with a generally strong family history of disease. We have analysed six multiplex families for missense variants using whole exome sequencing to find 32 rare heterozygous mutations shared amongst affected members. Included in these mutations was the KCNJ15 p.R28C variant, identified in five affected members of the same family, two elderly unaffected members of the same family, and two unrelated PD cases. Additionally, the SIPA1L1 p.R236Q variant was identified in three related affected members and an unrelated familial case. While the evidence presented here is not sufficient to assign causality to these rare variants, it does provide novel candidates for hypothesis testing in other modestly sized families with a strong family history. Future analysis will include characterisation of functional consequences and assessment of carriers in other familial cases.

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Sequential filtering for clinically relevant variants as a method for clinical interpretation of whole exome sequencing findings in glioma

BMC Medical Genomics ◽

10.1186/s12920-021-00904-3 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Ege Ülgen ◽

Özge Can ◽

Kaya Bilguvar ◽

Cemaliye Akyerli Boylu ◽

Şirin Kılıçturgay Yüksel ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Clinical Analysis ◽

Clinical Interpretation ◽

Germline Variants ◽

Whole Exome ◽

Gene Level ◽

Analysis Workflow ◽

Tumor Mutational Burden ◽

Diffuse Gliomas

Abstract Background In the clinical setting, workflows for analyzing individual genomics data should be both comprehensive and convenient for clinical interpretation. In an effort for comprehensiveness and practicality, we attempted to create a clinical individual whole exome sequencing (WES) analysis workflow, allowing identification of genomic alterations and presentation of neurooncologically-relevant findings. Methods The analysis workflow detects germline and somatic variants and presents: (1) germline variants, (2) somatic short variants, (3) tumor mutational burden (TMB), (4) microsatellite instability (MSI), (5) somatic copy number alterations (SCNA), (6) SCNA burden, (7) loss of heterozygosity, (8) genes with double-hit, (9) mutational signatures, and (10) pathway enrichment analyses. Using the workflow, 58 WES analyses from matched blood and tumor samples of 52 patients were analyzed: 47 primary and 11 recurrent diffuse gliomas. Results The median mean read depths were 199.88 for tumor and 110.955 for normal samples. For germline variants, a median of 22 (14–33) variants per patient was reported. There was a median of 6 (0–590) reported somatic short variants per tumor. A median of 19 (0–94) broad SCNAs and a median of 6 (0–12) gene-level SCNAs were reported per tumor. The gene with the most frequent somatic short variants was TP53 (41.38%). The most frequent chromosome-/arm-level SCNA events were chr7 amplification, chr22q loss, and chr10 loss. TMB in primary gliomas were significantly lower than in recurrent tumors (p = 0.002). MSI incidence was low (6.9%). Conclusions We demonstrate that WES can be practically and efficiently utilized for clinical analysis of individual brain tumors. The results display that NOTATES produces clinically relevant results in a concise but exhaustive manner.

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Management of individuals with germline variants in PALB2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

Genetics in Medicine ◽

10.1038/s41436-021-01151-8 ◽

2021 ◽

Author(s):

Marc Tischkowitz ◽

◽

Judith Balmaña ◽

William D. Foulkes ◽

Paul James ◽

...

Keyword(s):

Clinical Practice ◽

Medical Genetics ◽

Germline Variants ◽

Genetics And Genomics

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Extended gene panel testing in lobular breast cancer

Familial Cancer ◽

10.1007/s10689-021-00241-5 ◽

2021 ◽

Author(s):

Elke M. van Veen ◽

D. Gareth Evans ◽

Elaine F. Harkness ◽

Helen J. Byers ◽

Jamie M. Ellingford ◽

...

Keyword(s):

Breast Cancer ◽

Genetic Testing ◽

Detection Rate ◽

Gene Panel ◽

Lobular Breast Cancer ◽

Germline Variants ◽

Panel Testing ◽

Pathogenic Variants ◽

Gene Panel Testing ◽

Increased Risk

AbstractPurpose: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC. Methods: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53.Results: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83–66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58–23.95; P < 0.0001); and ATM: OR = 8.01 (95%CI 2.52–29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2. Conclusion: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.

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