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Systematic large-scale study of the inheritance mode of Mendelian disorders provides new insight into human diseasome.

ABSTRACT: One important piece of information about the human Mendelian disorders is the mode of inheritance. Recent studies of human genetic diseases on a large scale have provided many novel insights into the underlying molecular mechanisms. However, most successful analyses ignored the mode of inheritance of diseases, which severely limits our understanding of human disease mechanisms relating to the mode of inheritance at the large scale. Therefore, we here conducted a systematic large-scale study of the inheritance mode of Mendelian disorders, to bring new insight into human diseases. Our analyses include the comparison between dominant and recessive disease genes on both genomic and proteomic characteristics, Mendelian mutations, protein network properties and disease connections on both the genetic and the population levels. We found that dominant disease genes are more functionally central, topological central and more sensitive to disease outcome. On the basis of these findings, we suggested that dominant diseases should have higher genetic heterogeneity and should have more comprehensive connections with each other compared with recessive diseases, a prediction we confirm by disease network and disease comorbidity.

SUBMITTER: Hao D

PROVIDER: S-EPMC4200425 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Systematic large-scale study of the inheritance mode of Mendelian disorders provides new insight into human diseasome.

Hao Dapeng D Wang Guangyu G Yin Zuojing Z Li Chuanxing C Cui Yan Y Zhou Meng M

European journal of human genetics : EJHG 20140122 11

One important piece of information about the human Mendelian disorders is the mode of inheritance. Recent studies of human genetic diseases on a large scale have provided many novel insights into the underlying molecular mechanisms. However, most successful analyses ignored the mode of inheritance of diseases, which severely limits our understanding of human disease mechanisms relating to the mode of inheritance at the large scale. Therefore, we here conducted a systematic large-scale study of t ...[more]

PMID: 24448549

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Project description:BackgroundCongenital hydrocephalus is characterized by ventriculomegaly, defined as a dilatation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid (CSF) homeostasis. Primary congenital hydrocephalus is a subset of cases with prenatal onset and absence of another primary cause, e.g., brain hemorrhage. Published series report a Mendelian cause in only a minority of cases. In this study, we analyzed exome data of PCH patients in search of novel causal genes and addressed the possibility of an underlying oligogenic mode of inheritance for PCH.Materials and methodsWe sequenced the exome in 28 unrelated probands with PCH, 12 of whom from families with at least two affected siblings and 9 of whom consanguineous, thereby increasing the contribution of genetic causes. Patient exome data were first analyzed for rare (MAF < 0.005) transmitted or de novo variants. Population stratification of unrelated PCH patients and controls was determined by principle component analysis, and outliers identified using Mahalanobis distance 5% as cutoff. Patient and control exome data for genes biologically related to cilia (SYScilia database) were analyzed by mutation burden test.ResultsIn 18% of probands, we identify a causal (pathogenic or likely pathogenic) variant of a known hydrocephalus gene, including genes for postnatal, syndromic hydrocephalus, not previously reported in isolated PCH. In a further 11%, we identify mutations in novel candidate genes. Through mutation burden tests, we demonstrate a significant burden of genetic variants in genes coding for proteins of the primary cilium in PCH patients compared to controls.ConclusionOur study confirms the low contribution of Mendelian mutations in PCH and reports PCH as a phenotypic presentation of some known genes known for syndromic, postnatal hydrocephalus. Furthermore, this study identifies novel Mendelian candidate genes, and provides evidence for oligogenic inheritance implicating primary cilia in PCH.

Project description:Parkinson's disease is a common, progressive neurodegenerative disorder, affecting 3% of those older than 75 years of age. Clinically, Parkinson's disease (PD) is associated with resting tremor, postural instability, rigidity, bradykinesia, and a good response to levodopa therapy. Over the last 15 years, numerous studies have confirmed that genetic factors contribute to the complex pathogenesis of PD. Highly penetrant mutations producing rare, monogenic forms of the disease have been discovered in singular genes such as SNCA, Parkin, DJ-1, PINK 1, LRRK2, and VPS35. Unique variants with incomplete penetrance in LRRK2 and GBA have been shown to be strong risk factors for PD in certain populations. Additionally, over 20 common variants with small effect sizes are now recognized to modulate the risk for PD. Investigating Mendelian forms of PD has provided precious insight into the pathophysiology that underlies the more common idiopathic form of disease; however, no treatment methodologies have developed. Furthermore, for identified common risk alleles, the functional basis underlying risk principally remains unknown. The challenge over the next decade will be to strengthen the findings delivered through genetic discovery by assessing the direct, biological consequences of risk variants in tandem with additional high-content, integrated datasets. This review discusses monogenic risk factors and mechanisms of Mendelian inheritance of Parkinson disease. Highly penetrant mutations in SNCA, Parkin, DJ-1, PINK 1, LRRK2 and VPS35 produce rare, monogenic forms of the disease, while unique variants within LRRK2 and GBA show incomplete penetrance and are strong risk factors for PD. Additionally, over 20 common variants with small effect sizes modulate disease risk. The challenge over the next decade is to strengthen genetic findings by assessing direct, biological consequences of risk variants in tandem with high-content, integrated datasets. This article is part of a special issue on Parkinson disease.

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Systematic large-scale study of the inheritance mode of Mendelian disorders provides new insight into human diseasome.

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Systematic large-scale study of the inheritance mode of Mendelian disorders provides new insight into human diseasome.

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