Exome sequencing in individuals with cardiovascular laterality defects identifies potential candidate genes

Related Experiment Video

Updated: Sep 25, 2025

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
06:41

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila

Published on: August 20, 2019

13.8K

Katinka Breuer1,2, Korbinian M Riedhammer3,4, Nicole Müller2

  • 1Institute of Human Genetics, University Hospital of Bonn, Bonn, Germany.

European Journal of Human Genetics : EJHG
|April 27, 2022
PubMed

Insights

Laterality defects, often linked to congenital heart defects, were investigated using exome sequencing. This study identified potential new genes, DNAH17, LMBRD1, and WDR47, involved in these complex conditions.

Area of Science:

  • Genetics and Developmental Biology
  • Medical Genetics
  • Human Physiology

Background:

  • Laterality defects, occurring in approximately 1.1/10,000 births, present diverse phenotypes including situs inversus totalis and heterotaxy.
  • These defects are frequently associated with complex congenital heart defects (CHD) and visceral abnormalities like intestinal malrotation and asplenia.
  • A subset of laterality defects is linked to primary ciliary dyskinesia (PCD), presenting with respiratory issues or infertility.

Purpose of the Study:

  • To investigate the genetic underpinnings of laterality defects, excluding primary ciliary dyskinesia (PCD) cases.
  • To identify novel genes associated with cardiovascular laterality defects through exome sequencing.
  • To analyze variants in known and potential new genes implicated in laterality disorders.

Main Methods:

  • Exome sequencing (ES) was performed on 14 case-parent trios/quattros with laterality defects, with prior clinical exclusion of PCD.
  • Comprehensive clinical phenotyping included physical examination, echocardiography, and abdominal ultrasound.
  • Variant analysis focused on monoallelic de novo, rare biallelic, and X-linked recessive variants, supplemented by a survey of 2,109 individual exomes.

Main Results:

  • Rare variants of uncertain significance (VUS) were found in PKD1L1 and ZIC3 in two families.
  • Biallelic variants in LMBRD1 and DNAH17 were prioritized in two families, and an ultra-rare de novo variant in WDR47 was identified in another.
  • A broader exome survey identified novel monoallelic variants in WDR47 in two individuals with situs inversus totalis, heterotaxy, or isolated CHD.

Conclusions:

  • Exome sequencing in 14 families with cardiovascular laterality defects identified VUS in known genes (PKD1L1, ZIC3).
  • The study suggests DNAH17, LMBRD1, and WDR47 as potential candidate genes involved in laterality defects.
  • Further investigation is warranted to confirm the role of these candidate genes in the etiology of laterality disorders.

More Related Videos

Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information09:37

Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information

Published on: August 15, 2019

9.9K
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation07:15

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

Published on: January 16, 2019

11.1K

Related Concept Videos

Pleiotropy01:33

Pleiotropy

Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause Waardenburg Syndrome Type 4, or WS4, which can cause defects in pigmentation, hearing impairments, and an absence of intestinal contractions necessary for elimination. This diversity of phenotypes results from the expression pattern of SOX10 in early embryonic and fetal development. SOX10 is found in neural crest cells that form melanocytes,...
41.3K
Genome-wide Association Studies-GWAS01:11

Genome-wide Association Studies-GWAS

Genome-wide association studies or GWAS are used to identify whether common SNPs are associated with certain diseases. Suppose specific SNPs are more frequently observed in individuals with a particular disease than those without the disease. In that case, those SNPs are said to be associated with the disease. Chi-square analysis is performed to check the probability of the allele likely to be associated with the disease.
GWAS does not require the identification of the target gene involved in...
14.5K
X-linked Traits01:19

X-linked Traits

In most mammalian species, females have two X sex chromosomes and males have an X and Y. As a result, mutations on the X chromosome in females may be masked by the presence of a normal allele on the second X. In contrast, a mutation on the X chromosome in males more often causes observable biological defects, as there is no normal X to compensate. Trait variations arising from mutations on the X chromosome are called “X-linked”.
55.5K
Cardiomyopathy III: Hypertrophic Cardiomyopathy01:29

Cardiomyopathy III: Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy, or HCM, is an autosomal dominant genetic disorder characterized by asymmetric left ventricular hypertrophy without ventricular dilation. It is more common in men and is typically diagnosed in young, athletic adults.EtiologyHCM is primarily genetic and is caused by mutations in genes encoding sarcomeric proteins. Researchers have identified over 1400 mutations across at least 11 different genes. Among these, the most frequently occurring mutations are found in the...
73
Sex-linked Disorders01:43

Sex-linked Disorders

Like autosomes, sex chromosomes contain a variety of genes necessary for normal body function. When a mutation in one of these genes results in biological deficits, the disorder is considered sex-linked.
103.2K