Variation p.R1045H in MYH7 correlated with hypertrophic cardiomyopathy in a Chinese pedigree

2020 ◽  
Author(s):  
Yan Zhang ◽  
Shang Yiyi ◽  
Luo Liu ◽  
Xiaoxue Ding ◽  
Haiyan Wu ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Family History ◽  
Genetic Factors ◽  
Genetic Variant ◽  
Heart Function ◽  
Pedigree Analysis ◽  
Genetic Defects ◽  
Fatal Disease ◽  
Whole Exome

Abstract Objective: Inherited hypertrophic cardiomyopathy (HCM) is s a fatal disease that damages heart function and may cause the heart to stop beating suddenly. The genetic factors play an important role in HCM. Pedigree analysis is a good way to identify the genetic defects that cause disease. Methods: A HCM pedigree was found in Yunnan of China. Whole-exome sequencings were performed for finding the genetic variant of HCM. Another 30 HCM patients and 200 health controls were also used to investigate the frequency of variation by TaqMan-MGB method. Results: The variation NM_000257.4:c.3134G>A (NP_000248.2:p.Arg1045His, rs397516178, short as c.3134G>A) was found to co-segregate with the symptoms of HCM. Meanwhile, the variation was not found in 200 controls. After genotyping the variation in 30 HCM patients, one patient carried the variation and had a family history. Conclusion: Our findings support that this variation may be closely related to the occurrence of the disease. According the ACMG guideline, the c. 3134G>A should be classified as " Likely pathogenic".

scholarly journals Variation p.R1045H in MYH7 correlated with hypertrophic cardiomyopathy in a Chinese pedigree

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yan Zhang ◽  
Yiyi Shang ◽  
Luo Liu ◽  
Xiaoxue Ding ◽  
Haiyan Wu ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Genetic Variants ◽  
Genetic Factors ◽  
Clinical Phenotype ◽  
Heart Function ◽  
Pedigree Analysis ◽  
Muscle Disease ◽  
Genetic Defects ◽  
Healthy Controls ◽  
Whole Exome

Abstract Background Inherited hypertrophic cardiomyopathy (HCM) is a common heart muscle disease that damages heart function and may cause the heart to suddenly stop beating. Genetic factors play an important role in HCM. Pedigree analysis is a good way to identify the genetic defects that cause disease. Methods An HCM pedigree was determined in Yunnan, China. Whole-exome sequencing was performed to identify the genetic variants of HCM. Another 30 HCM patients and 200 healthy controls were also used to investigate the frequency of the variants by customized TaqMan genotyping assay. Results The variant NM_000257.4:c.3134G > A (NP_000248.2:p.Arg1045His, rs397516178, c.3134G > A in short) was found to cosegregate with the clinical phenotype of HCM. Moreover, the variant was not found in the 200 control subjects. After genotyping the variant in 30 HCM patients, there was one patient who carried the variant and had a family history. Conclusions Our findings suggest that this variant may be closely related to the occurrence of the disease. According the ACMG guidelines, the c.3134G > A variant should be classified as "Likely pathogenic".

Importance of Family History in the Era of Exome Analysis: A Report of a Family with Multiple Concurrent Genetic Diseases

2021 ◽  
Vol 86 (1-4) ◽  
pp. 28-33
Author(s):  
Karishma Mahtani ◽  
Diana Park ◽  
Jessica Abbott ◽  
Pavalan Panneer Selvam ◽  
Paldeep S. Atwal
Keyword(s):  
Prostate Cancer ◽  
Family History ◽  
Genetic Disorders ◽  
Genetic Diseases ◽  
Pedigree Analysis ◽  
Single Patient ◽  
Disease Etiology ◽  
Whole Exome ◽  
Exome Analysis ◽  
Dependent Processes

Multiple familial diseases in a single patient often present with overlapping symptomatology that confers difficulty in delineating a clinical diagnosis. Pedigree analysis has been a long-standing practice in the field of medical genetics to discover familial diseases. In recent years, whole exome sequencing (WES) has proven to be a useful tool for aiding physicians in diagnosing and understanding disease etiology. This report shows that pedigree analysis and WES are co-dependent processes in establishing diagnoses in a family with 4 different genetic disorders: Birt-Hogg-Dubé Syndrome, <i>RRM2B</i>-related mitochondrial disease, <i>CDC73</i>-related primary hyperparathyroidism, and familial prostate cancer.

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

Genes ◽  
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.

Social Dimensions of Genetic Disorders

1992 ◽  
Vol 14 (1) ◽  
pp. 10-13 ◽  
Author(s):  
Joan Ablon
Keyword(s):  
Health Education ◽  
Infant Mortality ◽  
Genetic Disease ◽  
Genetic Factors ◽  
Genetic Disorders ◽  
Genetic Defects ◽  
Social Dimensions ◽  
Live Births ◽  
Department Of Health ◽  
Recessive Genes

Each of us carries between 4-8 recessive genes for serious genetic defects, and, hence, stands a statistical chance of passing on a serious or lethal condition to each child… 12 million Americans carry true genetic disease due wholly or partly to defective genes or chromosomes…40 percent or more of all infant mortality results from genetic factors…4.8 to 5 percent of all live births have genetic defects. (U.S. Department of Health, Education, and Welfare. "What are the Facts About Genetic Disease?" National Inst. of Gen. Med. Scs., P.H.S., N.I.H. DHEW Pub. No. (NIH), 75-370, 1975.)

scholarly journals Serial Observations and Mutational Analysis of an Adoptee with Family History of Hypertrophic Cardiomyopathy

2010 ◽  
Vol 2010 ◽  
pp. 1-4
Author(s):  
Bronwyn Harris ◽  
Jean P. Pfotenhauer ◽  
Cheri A. Silverstein ◽  
Larry W. Markham ◽  
Kim Schafer ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Hypertrophic Cardiomyopathy ◽  
Family History ◽  
Mutational Analysis ◽  
Clinical Findings ◽  
Dominant Mode ◽  
Natural Mother ◽  
History Of ◽  
In Cis ◽  
Inherited Cardiac Disease

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disease with an autosomal dominant mode of transmission. Comprehensive genetic screening of several genes frequently found mutated in HCM is recommended for first-degree relatives of HCM patients. Genetic testing provides the means to identify those at risk of developing HCM and to institute measures to prevent sudden cardiac death (SCD). Here, we present an adoptee whose natural mother and maternal relatives were known be afflicted with HCM and SCD. The proband was followed closely from age 6 to 17 years, revealing a natural history of the progression of clinical findings associated with HCM. Genetic testing of the proband and her natural mother, who is affected by HCM, revealed that they were heterozygous for both the R719Q and T1513S variants in the cardiac beta-myosin heavy chain (MYH7) gene. The proband's ominous family history indicates that the combination of the R719Q and T1513S variantsin cismay be a “malignant” variant that imparts a poor prognosis in terms of the disease progression and SCD risk.

scholarly journals Prenatal Diagnosis of Birth Defects by Exome Sequencing

2021 ◽  
Vol 2 (1) ◽  
pp. 5
Author(s):  
Sara Mumtaz ◽  
Huma Shehwana ◽  
Sabba Mehmood
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Birth Defects ◽  
Prenatal Screening ◽  
Chorionic Villus ◽  
Genetic Defects ◽  
Chorionic Villus Sampling ◽  
Prenatal Period ◽  
Early Management ◽  
Whole Exome

Prenatal screening and diagnosis are increasingly becoming a part of medical practice. Prenatal screening can reduce the incidence of birth defects which cause morbidity and mortality in newborns. With emerging technologies, now it is possible to diagnose the genetic basis of birth defects more accurately in the prenatal period for early management. Different approaches are available for detecting genetic defects at different levels like karyotyping, chromosomal microarrays and Sanger sequencing. However, many cases still remain undiagnosed. Next generation sequencing has revolutionized the field of genetics that can detect genetic defects at the level of a single base pair. It includes both whole exome sequencing (WES) and whole genome sequencing (WGS). WES has particularly accelerated the discovery of disease-causing variants in many monogenic anomalies postnatally. Research is being conducted on the use of whole exome sequencing in the prenatal diagnostics of genetic anomalies detected by ultrasound. It is a more efficient way of getting an insight into the molecular basis of birth defects compared with conventional genetic approaches. However, technical and ethical issues need to be addressed before introducing this technique into routine prenatal clinical practice. Fetal cell sampling is done by invasive medical procedures like amniocentesis or chorionic villus sampling. However, noninvasive strategy of collecting fetal DNA from maternal plasma is an exciting and emerging domain. It is evident that in the coming years, we shall be able to use these techniques in the routine clinical setting and to improve the diagnosis and management of birth disorders during prenatal period.

scholarly journals Identification of MYOM2 as a candidate gene in hypertrophic cardiomyopathy and Tetralogy of Fallot, and its functional evaluation in the Drosophila heart

2020 ◽  
Vol 13 (12) ◽  
pp. dmm045377
Author(s):  
Emilie Auxerre-Plantié ◽  
Tanja Nielsen ◽  
Marcel Grunert ◽  
Olga Olejniczak ◽  
Andreas Perrot ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Candidate Gene ◽  
Tetralogy Of Fallot ◽  
Heart Function ◽  
Heart Diseases ◽  
Critical Role ◽  
Disease Genes ◽  
Compound Heterozygous ◽  
Functional Evaluation ◽  
Myosin Binding

ABSTRACTThe causal genetic underpinnings of congenital heart diseases, which are often complex and multigenic, are still far from understood. Moreover, there are also predominantly monogenic heart defects, such as cardiomyopathies, with known disease genes for the majority of cases. In this study, we identified mutations in myomesin 2 (MYOM2) in patients with Tetralogy of Fallot (TOF), the most common cyanotic heart malformation, as well as in patients with hypertrophic cardiomyopathy (HCM), who do not exhibit any mutations in the known disease genes. MYOM2 is a major component of the myofibrillar M-band of the sarcomere, and a hub gene within interactions of sarcomere genes. We show that patient-derived cardiomyocytes exhibit myofibrillar disarray and reduced passive force with increasing sarcomere lengths. Moreover, our comprehensive functional analyses in the Drosophila animal model reveal that the so far uncharacterized fly gene CG14964 [herein referred to as Drosophila myomesin and myosin binding protein (dMnM)] may be an ortholog of MYOM2, as well as other myosin binding proteins. Its partial loss of function or moderate cardiac knockdown results in cardiac dilation, whereas more severely reduced function causes a constricted phenotype and an increase in sarcomere myosin protein. Moreover, compound heterozygous combinations of CG14964 and the sarcomere gene Mhc (MYH6/7) exhibited synergistic genetic interactions. In summary, our results suggest that MYOM2 not only plays a critical role in maintaining robust heart function but may also be a candidate gene for heart diseases such as HCM and TOF, as it is clearly involved in the development of the heart.This article has an associated First Person interview with Emilie Auxerre-Plantié and Tanja Nielsen, joint first authors of the paper.

scholarly journals Association between family history and the onset age of essential hypertension in Han population in Shanghai China

2019 ◽  
Author(s):  
li anle ◽  
Qian Peng ◽  
Yue Qin Shao ◽  
Yi Ying Zhang ◽  
Fang Xiang
Keyword(s):  
Essential Hypertension ◽  
Family History ◽  
Genetic Factors ◽  
Nuclear Family ◽  
Age Of Onset ◽  
Control Group ◽  
Case Group ◽  
Onset Age ◽  
Han Population ◽  
The Difference

Abstract Importance Genetic factors are important influencing factors of essential hypertension, and family history (FH) is an important marker of genetic factors. Objective To explore the association between family history and the onset age of essential hypertension in Han population in Shanghai China. Methods According to l:l matched pairs design，342 precursor of hypertension and 342 controls were selected and investigate their nuclear family members in the case-control study. The diagnostic information of hypertension in all relatives of these two groups was investigated. The method of genetic epidemiology research was used to explore the effect of family history. Results The average prevalence of hypertension was 23.32%. The prevalence of hypertension of first-degree relatives was 33.99%; the prevalence of second- degree relatives was 17.60%; the prevalence of third-degree relatives was 13.51%. All prevalence of hypertension of case group relatives were significantly higher than that of control group relatives. The average onset age in population with positive FH is 48.74±11.16 years old, and the average onset age in population with negative FH is 54.38±9.87 years old. The difference about two FH groups showed statistically significant (t=4.589, P<0.001). The average onset age of offspring with father, mother, grandpa, grandma, maternal grandpa or maternal grandma positive was respectively 48.42± 11.16, 49.16±11.12, 39.55±11.95, 39.88±11.90, 43.67±9.77 or 43.64±10.21 years old; and the average onset age of children with father, mother, grandpa, grandma, maternal grandpa or maternal grandma negative was respectively 51.90± 10.81, 51.17±11.04, 51.07±10.59, 51.08±10.60, 50.50±11.09 or 50.57±11.06 years old. The difference about two groups showed statistically significant. Conclusion Family history has a positive effect on the occurrence of hypertension, and lead to earlier age of onset of offspring. The effects are different among parent and grandparent in Han in Shanghai China.

Abstract 16468: Results of Research Genetic Testing in Pediatric Cardiomyopathy Patients Justify Broader Clinical Genetic Testing

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Stephanie M Ware ◽  
Steven E Lipshultz ◽  
Steven D Colan ◽  
Ling Shi ◽  
Charles E Canter ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Risk Stratification ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Genetic ◽  
Clinical Genetic Testing ◽  
Whole Exome ◽  
Pediatric Cardiomyopathy ◽  
History Of

Introduction: Pediatric cardiomyopathies are genetically heterogeneous diseases with high risk of death or cardiac transplant. Despite progress in identifying causes, the majority of cases remain idiopathic. Currrently, genetic testing is not performed in all children with cardiomyopathy. Gene identification leads to better individual risk stratification and has the potential to stimulate the development of therapies based on the underlying mutation. The aim of this study is to identify genetic mutations in pediatric cardiomyopathy patients using whole exome sequencing. Hypothesis: Sarcomeric mutations are under-diagnosed causes of all forms of cardiomyopathy in children. Methods: Probands with cardiomyopathy were recruited from 11 institutions. Results of clinical genetic testing prior to enrollment were collected. Whole exome sequencing was performed and mutations were identified in 35 genes currently available on clinical genetic testing panels. Results: The initial 154 probands subjected to exome included 78 patients with DCM, 43 with HCM, 14 with RCM, and 19 with LVNC, mixed, or unknown types. Familial disease was present in 38% and the remainder were idiopathic. Twenty-seven percent had positive clinical genetic testing prior to enrollment. Exome testing identified mutations in 38 subjects who had not had clinical testing, increasing the cohort positive testing rate to 55% (DCM, 34.6%; HCM, 74.4%; RCM, 71.4%). Forty-five percent of subjects with no family history of disease had an identifiable mutation. Conclusions: Pediatric cardiomyopathy patients have a high incidence of mutations that can be identified by clinically available genetic testing. Lack of a family history of cardiomyopathy was not predictive of normal genetic testing. These results support the broader use of genetic testing in pediatric patients with all functional phenotypes of cardiomyopathy to identify disease causation allowing better family risk stratification.

Mutation of COL2A1 in a Chinese Family with Presentations of Legg-Calvé-Perthes Disease

2020 ◽  
Author(s):  
denglu yan ◽  
zhaojie Wang ◽  
Zhi Zhang
Keyword(s):  
Femoral Head ◽  
Sanger Sequencing ◽  
Structural Changes ◽  
Genetic Factors ◽  
Mutation Detection ◽  
Perthes Disease ◽  
Chinese Family ◽  
Col2a1 Gene ◽  
Whole Exome ◽  
Missense Substitution

Abstract Background: The aim of this study was to identify genetic factors and chromosomal regions contributing to osteonecrosis of the femoral head (ONFH) in a Chinese family with presentations of Legg-Calvé-Perthes Disease (LCDP). Methods: In this study, we performed whole exon sequencing of a Chinese family with LCPD for mutation detection. Ten members had ONFH in twenty-seven family members in four generations family, 5 unaffected members of the studied family and 5 normal peoples as control were underwent whole exome sequencing for mutation detection. Structural modeling test was applied to analyze the potential structural changes caused by the missense substitution. Results: In this Chinese family affected by LCPD, the mutation (c.3508 G>A, p. Gly1170Ser) in exon 50 of COL2A1 in the Gly–X–Y domain was present in 10 patients but absent in 5 unaffected members of the studied family and in 5 control chromosomes from unaffected individuals of matched geographical ancestry. The COL2A1 gene mutation was further validated by Sanger sequencing, confirmed that were heterozygous for the mutation. Then, we identified the p.Gly1170Ser mutation in exon 50 of COL2A1 in a Chinese family with LCPD. Conclusions: This study maps the mutation of mutation (c.3508 G>A, p. Gly1170Ser) in exon 50 of COL2A1 in the Gly–X–Y domain in a Chinese family of LCPD, which causes osteonecrosis of femoral head.

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