Clinical Implications of Identifying Pathogenic Variants in Individuals With Thoracic Aortic Dissection

Background: Thoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or family members. Methods: We performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity. Results: Twenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, and TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 versus 57 years), higher rates of root aneurysm (54% versus 30%), less hypertension (15% versus 57%), lower rates of smoking (19% versus 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed that pathogenic variant carrier status was significantly associated with age <50 (odds ratio [OR], 5.5; 95% CI, 1.6–19.7), no history of hypertension (OR, 5.6; 95% CI, 1.4–22.3), and family history of aortic disease (mother: OR, 5.7; 95% CI, 1.4–22.3, siblings: OR, 5.1; 95% CI, 1.1–23.9, children: OR, 6.0; 95% CI, 1.4–26.7). Conclusions: Clinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with a thoracic aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset <50 years, family history of thoracic aortic disease, and no history of hypertension.

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Clinical implications of identifying pathogenic variants in aortic dissection patients with whole exome sequencing

10.1101/497917 ◽

2018 ◽

Author(s):

Brooke N. Wolford ◽

Whitney E. Hornsby

Keyword(s):

Family History ◽

Aortic Dissection ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Family Members ◽

Aortic Disease ◽

Thoracic Aortic Dissection ◽

Pathogenic Variants ◽

Whole Exome ◽

History Of

ABSTRACTBackgroundThoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or their family members.MethodsWe performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity.ResultsTwenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 vs. 57 years), higher rates of root aneurysm (54% vs. 30%), less hypertension (15% vs. 57%), lower rates of smoking (19% vs. 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed significant risk factors associated with pathogenic variants are age <50 [odds ratio (OR) = 5.5; 95% CI: 1.6-19.7], no history of hypertension (OR=5.6; 95% CI: 1.4-22.3) and family history of aortic disease (mother: OR=5.7; 95% CI: 1.4-22.3, siblings: OR=5.1; 95% CI 1.1-23.9, children: OR=6.0; 95% CI: 1.4-26.7).ConclusionsClinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset of aortic dissection <50 years old, family history of aortic disease, and no history of hypertension.

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Familial pancreatic cancer with PALB2 and NBN pathogenic variants: a case report

Hereditary Cancer in Clinical Practice ◽

10.1186/s13053-020-00160-z ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Kodai Abe ◽

Arisa Ueki ◽

Yusaku Urakawa ◽

Minoru Kitago ◽

Tomoko Yoshihama ◽

...

Keyword(s):

Pancreatic Cancer ◽

Family History ◽

Genetic Analysis ◽

Pathogenic Variant ◽

Familial Pancreatic Cancer ◽

Case Presentation ◽

Pathogenic Variants ◽

Pancreatic Cancers ◽

Epidemiological Surveys ◽

History Of

Abstract Background Family history is one of the risk factors for pancreatic cancer. It is suggested that patients with pancreatic cancer who have a familial history harbor germline pathogenic variants of BRCA1 and/or BRCA2 (BRCA1/2), PALB2, or ATM. Recently, some germline variants of familial pancreatic cancers (FPCs), including PALB2, have been detected. Several countries, including Japan, perform screening workups and genetic analysis for pancreatic cancers. We have been carrying out active surveillance for FPC through epidemiological surveys, imaging analyses, and genetic analysis. Case presentation Here, we present the case of a female patient harboring pathogenic variants of PALB2 and NBN, with a family history of multiple pancreatic cancer in her younger brother, her aunt, and her father. Moreover, her father harbored a PALB2 pathogenic variant and her daughter harbored the same NBN pathogenic variant. Given the PALB2 and NBN variants, we designed surveillance strategies for the pancreas, breast, and ovary. Conclusions Further studies are required to develop strategies for managing FPCs to facilitate prompt diagnosis before their progression.

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Germinal defects of SDHx genes in patients with isolated pituitary adenoma

Acta Endocrinologica ◽

10.1530/eje-20-0054 ◽

2020 ◽

Vol 183 (4) ◽

pp. 369-379

Author(s):

Grégory Mougel ◽

Arnaud Lagarde ◽

Frédérique Albarel ◽

Wassim Essamet ◽

Perrine Luigi ◽

...

Keyword(s):

Genetic Testing ◽

Pituitary Adenoma ◽

Family History ◽

Age Of Onset ◽

Personal History ◽

Pathogenic Variants ◽

Predisposing Genes ◽

History Of ◽

New Gateway

Background: The ‘3PAs’ syndrome, associating pituitary adenoma (PA) and pheochromocytoma/paraganglioma (PPGL), is sometimes associated with mutations in PPGL-predisposing genes, such as SDHx or MAX. In ’3PAs’ syndrome, PAs can occur before PPGL, suggesting a new gateway into SDHx/MAX-related diseases. Objective: To determine the SDHx/MAX mutation prevalence in patients with isolated PAs and characterize PAs of patients with SDHx/MAX mutations. Design: Genes involved in PAs (AIP/MEN1/CDKN1B) or PPGLs (SDHx/MAX) were sequenced in patients with isolated PAs. We then conducted a review of cases of PA in the setting of ’3PAs’ syndrome. Results: A total of 263 patients were recruited. Seven (likely) pathogenic variants were found in AIP, two in MEN1, two in SDHA, and one in SDHC. The prevalence of SDHx mutations reached 1.1% (3/263). Of 31 reported patients with PAs harboring SDHx/MAX mutations (28 published cases and 3 cases reported here), 6/31 (19%) developed PA before PPGL and 8/31 (26%) had isolated PA. The age of onset was later than in patients with AIP/MEN1 mutations. PAs were mainly macroprolactinomas and showed intracytoplasmic vacuoles seen on histopathology. Conclusions: We discovered SDHx mutations in patients bearing PA who had no familial or personal history of PPGL. However, the question of incidental association remains unresolved and data to determine the benefit of SDHx/MAX screening in these patients are lacking. We recommend that patients with isolated PA should be carefully examined for a family history of PPGLs. A family history of PPGL, as well as the presence of intracytoplasmic vacuoles in PA, requires SDHx/MAX genetic testing of patients.

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Correlation between Family RB1 Gene Pathogenic Variant with Clinical Features and Prognosis of Retinoblastoma under 5 Years Old

Disease Markers ◽

10.1155/2021/9981028 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Yi Zhang ◽

Yizhuo Wang ◽

Dongsheng Huang ◽

Jianmin Ma ◽

Weiling Zhang ◽

...

Keyword(s):

Family History ◽

Clinical Phenotype ◽

Acid Sites ◽

Pathogenic Variant ◽

Rb1 Gene ◽

Genetic History ◽

High Risk Factors ◽

Pathogenic Variants ◽

History Of ◽

Hereditary Tumors

Retinoblastoma (RB) is the most common primary intraocular malignant tumor in infants and the prototype of human hereditary tumors. Its occurrence and development are closely related to the pathogenic variant of tumor suppressor RB1 gene. We aim to analyze the characteristics of RB1 gene pathogenic variant and clinical phenotype in retinoblastoma patients and their relatives. Children with RB were recruited from August 2007 to November 2017. QT-PCR, probing, and gene sequencing were used to analyze the sequence of RB1 gene in RB children, their parents, or grandparents with a clear history of illness. The SPSS20.0 software was used to analyze the correlation between polymorphisms of RB1 gene and the incidence and prognosis of the enrolled children and relatives. 40 RB children (20 males and 20 females) were recruited, unilateral RB accounted for 52.5% (21/40), bilateral RB accounted for 42.5% (17/40), and trilateral RB accounted for 5.0% (2/40). 6 patients had a clear family history (15.0%, 6/40). It had been verified that 19 probands (47.5%) have RB1 gene pathogenic variants (11 frameshift and 8 missense pathogenic variants), of which germline inheritance accounted for 47.4% (9/19) and nongermline heredity accounted for 52.6% (10/19). Pathogenic variants of 10 nucleic acid sites without reported were found, among which c.2455C>G (p.L819V) was confirmed to have heterozygous pathogenic variants in both a bilateral RB patient and his mother with unilateral RB. Family genetic high-risk factors, bilateral/trilateral RB, >12-month-onset RB have a higher proportion of RB1 gene pathogenic variant than children with no family history, unilateral RB, and ≤12-month ( P = 0.021 , 0.001,0.034). The proportion of pedigree inheritance of infantile retinoblastoma with bilateral disease is high. There was a certain proportion of RB1 gene pathogenic variant in 3-5-year-old children with bilateral RB, even if they had no family genetic history. Therefore, the detection of RB1 gene pathogenic variant should not only focus on infants but also on the phenotype of RB1 gene pathogenic variant in children over 3 years old with bilateral eye disease.

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Coffin-Lowry preprint 2018

10.31219/osf.io/6scqn ◽

2018 ◽

Author(s):

Paolo Moretti

Keyword(s):

Family History ◽

Clinical Features ◽

De Novo ◽

Severe Disease ◽

Immunosuppressive Treatment ◽

Pathogenic Variant ◽

First Degree Relatives ◽

Pathogenic Variants ◽

History Of ◽

Psychiatric Manifestations

Coffin-Lowry syndrome is an X-linked disease caused by pathogenic variants in RPS6KA3. The disease generally causes severe neurologic and non-neurologic abnormalities in males, and more variable phenotypes in females, including psychiatric manifestations. The majority of cases occur in the absence of known family history of the disease, and women carrying a de novo pathogenic variant may be undiagnosed due to the absence of severe disease manifestations or typically affected first-degree relatives. We describe the clinical features of a woman of normal intellect carrying a novel RPS6KA3 pathogenic variant in whom psychiatric manifestations and encephalopathy responded to immunosuppressive treatment.

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Case Report: The Role of Molecular Analysis of the MUTYH Gene in Asymptomatic Individuals

Frontiers in Genetics ◽

10.3389/fgene.2020.590486 ◽

2020 ◽

Vol 11 ◽

Author(s):

Katarína Fabišíková ◽

Olívia Hamidová ◽

Regína Lohajová Behulová ◽

Katarína Závodná ◽

Petra Priščáková ◽

...

Keyword(s):

Family History ◽

Molecular Analysis ◽

Excision Repair ◽

Dna Lesions ◽

Pathogenic Variant ◽

Sequencing Analysis ◽

Biallelic Mutation ◽

Pathogenic Variants ◽

Mutyh Gene ◽

History Of

MUTYH-associated polyposis (MAP) is a rare hereditary condition caused by the biallelic mutation in the MUTYH gene encoding MUTYH glycosylase. This enzyme is a key member of the base excision repair (BER) pathway responsible for the repair of DNA lesions formed by reactive oxygen species (ROS). We report two cases of MAP. In case 1, a 67-year-old woman who presented with a personal history of colorectal and endometrial cancer and a family history of cancer syndromes underwent multigene panel testing that revealed a germline homozygous (biallelic) pathogenic variant c.1187G > A (p.Gly396Asp) in the MUTYH gene. Subsequent sequencing analysis performed in the offspring of the proband identified all three asymptomatic offspring as carriers of this pathogenic variant. In case 2, a 40-year-old woman with a strong family history of colorectal cancer [the proband’s sister was a carrier of the pathogenic variant c.536A > G (p.Tyr179Cys) of the MUTYH gene] and renal cancer underwent sequencing analysis of the MUTYH gene. The pathogenic heterozygous (monoallelic) variant c.536A > G (p.Tyr179Cys) of the MUTYH gene was identified in the proband. We found another pathogenic variant of the MUTYH gene—heterozygous (monoallelic) mutation c.1187G > A (p.Gly396Asp) in the genome of the proband’s husband. Molecular analysis of their offspring revealed that they are compound heterozygotes for MUTYH pathogenic variants c.536A > G (p.Tyr179Cys)/c.1187G > A (p.Gly396Asp). This paper shows the importance of genetic testing of asymptomatic relatives of the proband to ensure an early surveillance and management of individuals positive for pathogenic variant (s) in the MUTYH gene.

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KIF6 719Arg Genetic Variant and Risk for Thoracic Aortic Dissection

Aorta ◽

10.12945/j.aorta.2016.16.003 ◽

2016 ◽

Vol 04 (03) ◽

pp. 83-90 ◽

Cited By ~ 8

Author(s):

Olga Iakoubova ◽

Carmen Tong ◽

Joseph Catanese ◽

Charles Rowland ◽

May Luke ◽

...

Keyword(s):

Aortic Aneurysm ◽

Aortic Dissection ◽

Thoracic Aortic Aneurysm ◽

Genetic Variant ◽

The United States ◽

Aortic Disease ◽

Carrier Status ◽

Thoracic Aortic Disease ◽

Logistic Regression Models ◽

Thoracic Aortic Dissection

Background: Carriers of the 719Arg variant in KIF6, compared with noncarriers, have been reported to be at greater risk for coronary heart disease (CHD) in six prospective studies. Because CHD, thoracic aortic dissection, and nondissection thoracic aortic aneurysm share some risk factors and aspects of pathophysiology, we investigated whether carriers of the 719Arg variant also have greater odds of thoracic aortic dissection or nondissected thoracic aortic aneurysm than noncarriers. Methods: We genotyped 140 thoracic aortic dissection cases, 497 nondissection thoracic aortic aneurysm cases, and 275 disease-free controls collected in the United States, Hungary, and Greece and investigated the association between KIF6 719Arg carrier status and thoracic aortic dissection, and between KIF6 719Arg carrier status and nondissection thoracic aortic aneurysm, using logistic regression models adjusted for age, sex, hypertension, smoking, and country. Results: The odds of aortic dissection were two-fold greater in KIF6 719Arg carriers compared with noncarriers (odds ratio (OR) 2.14, 95% confidence interval (CI) 1.18-3.9). To account for the potential of concomitant CHD to confound the association between the KIF6 719Arg and thoracic aortic dissection, we repeated the analysis after removing subjects with concomitant CHD; the estimates for association of KIF6 719Arg carrier status remained essentially the same (OR 2.04, 95% CI 1.11-3.77). In contrast, KIF6 719Arg carrier status was not associated with risk for nondissection thoracic aortic aneurysm. Conclusions: We observed an association of the KIF6 719Arg genetic variant with thoracic aortic dissection in this multicenter case-control study. This association may enhance our management of patients with thoracic aortic disease.

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Positive family history of aortic dissection dramatically increases dissection risk in family members

International Journal of Cardiology ◽

10.1016/j.ijcard.2017.04.080 ◽

2017 ◽

Vol 240 ◽

pp. 132-137 ◽

Cited By ~ 15

Author(s):

Wei-Guo Ma ◽

Alan S. Chou ◽

Salvior C.M. Mok ◽

Bulat A. Ziganshin ◽

Paris Charilaou ◽

...

Keyword(s):

Family History ◽

Aortic Dissection ◽

Positive Family History ◽

Family Members ◽

History Of

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Identification of c.1531C>T Pathogenic Variant in the CDH1 Gene as a Novel Germline Mutation of Hereditary Diffuse Gastric Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20204980 ◽

2019 ◽

Vol 20 (20) ◽

pp. 4980 ◽

Cited By ~ 2

Author(s):

Enrique Norero ◽

M. Alejandra Alarcon ◽

Christopher Hakkaart ◽

Tomas de Mayo ◽

Cecilia Mellado ◽

...

Keyword(s):

Gastric Cancer ◽

Family History ◽

Family Members ◽

Pathogenic Variant ◽

Hereditary Diffuse Gastric Cancer ◽

Diffuse Gastric Cancer ◽

Sequence Variant ◽

Diffuse Type ◽

Cdh1 Gene ◽

History Of

Germline pathogenic variants in the CDH1 gene are a well-established cause of hereditary diffuse gastric cancer (HDGC) syndrome. The aim of this study was to characterize CDH1 mutations associated with HDGC from Chile, a country with one of the highest incidence and mortality rates in the world for gastric cancer (GC). Here, we prospectively include probands with family history/early onset of diffuse-type of GC. The whole coding sequence of the CDH1 gene was sequenced from genomic DNA in all patients, and a multidisciplinary team managed each family member with a pathogenic sequence variant. Thirty-six cases were included (median age 44 years/male 50%). Twenty-seven (75%) patients had diffuse-type GC at ≤50 years of age and 19 (53%) had first or second-degree family members with a history of HDGC. Two cases (5.5%) carried a non-synonymous germline sequence variant in the CDH1 gene: (a) The c.88C>A missense variant was found in a family with three diffuse-type GC cases; and (b) c.1531C>T a nonsense pathogenic variant was identified in a 22-year-old proband with no previous family history of HDGC. Of note, six family members carry the same nonsense pathogenic variant. Prophylactic gastrectomy in the proband’s sister revealed stage I signet-ring cell carcinoma. The finding of 1531C>T pathogenic variant in the CDH1 in proband with no previous family history of HDGC warrants further study to uncover familial clustering of disease in CDH1 negative patients. This finding may be particularly relevant in high incidence countries, such as the case in this report.

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