Inheritance patterns in NGS-based Disease Diagnosis

Monika Opalek, PhD

June 29, 2023

Understanding the inheritance patterns of genes is particularly significant in the context of genetic diseases. The identification and classification of these patterns provide valuable insights into the likelihood of a genetic variant causing a disease. By incorporating zygosity and gene inheritance information, IntelliseqFlow workflows assign specific inheritance pattern matches to identified variants. This comprehensive approach enables a better understanding of the genetic underpinnings of diseases, facilitating more accurate diagnoses and personalized treatment strategies. 

Every individual possesses two copies of each autosomal gene, one inherited from their mother and one from their father. The inheritance patterns determine how the genetic traits are passed down from one generation to another and how they impact the individual's phenotype. Inheritance modes differ between autosomal and sex chromosomes, because females carry two copies of each X-linked gene, while males carry only one copy each of X-linked and Y-linked genes. The basic modes of inheritance include:

  • Autosomal Dominant Inheritance: Dominant genes and mutations are expressed even when there is only one copy present. Therefore, inheriting one copy of a damaged dominant gene is sufficient for a disease to develop.
  • Autosomal Recessive Inheritance: Recessive genes and mutations require two copies to be present for a phenotype to be expressed. If an individual has only one copy of a damaged recessive gene, they are carriers of the disease but do not exhibit any symptoms.
  • X-linked Dominant Inheritance: Dominant genes and mutations located on the X chromosome will affect the phenotypes of both males and females.
  • X-linked Recessive Inheritance: Recessive genes and mutations located on the X chromosome require two copies to be expressed in females, but only one copy to be expressed in males. Since males only have one X chromosome, any mutated gene on the X chromosome, even if recessive, will result in a disease.
  • Y-linked Inheritance: Genes and mutations located on the Y chromosome are expressed in males. Females do not carry the Y chromosome.
  • Mitochondrial Inheritance: The disease can develop both in males and females even when only a fraction of the mitochondria are affected by damaging mutations. All mitochondria are inherited from the mother, thus males do not pass the disease to the next generation

Determining the inheritance pattern of a gene or mutation is particularly significant in the context of diseases. Specifically, it helps determine whether an inherited genetic variant is dominant enough to cause the development of a disease. The HPO and OMIM databases collect information on the identified inheritance patterns of genes.

Within the IntelliseqFlow workflows, we assign an inheritance pattern match to each identified variant. We consider zygosity (GATK HaplotypeCaller) and the gene inheritance pattern (HPO database). This information indicates whether the patient's genotype is a probable cause of the disease, given the inheritance pattern of the damaged gene. We identify the following categories:

  • Dominant: assigned to heterozygous and homozygous genotypes within genes of dominant inheritance.
  • Possibly Dominant: assigned to heterozygous variants within a gene for which both dominant and recessive inheritance modes are assigned.
  • Recessive: assigned to homozygous variants of the gene with a recessive mode of inheritance.
  • Likely Compound Het: assigned to variants within a gene with a recessive inheritance pattern if we find more than one probably damaging variant of the gene. It's important to note that we do not know the phasing of the variants, and compound heterozygosity occurs only when variants are on different chromosomes and damage both copies of the gene.
  • Mitochondrial: assigned to all mitochondrial variants.
  • None: assigned to variants with genotypes insufficient to cause disease (for example, heterozygous variants within a gene having a recessive inheritance pattern)

The assignment of an inheritance pattern match serves as a valuable tool for evaluating the potential contribution of a specific variant to disease symptoms. The inheritance pattern match can be used to assess the likelihood that given variant is indeed causing the disease symptoms. For instance, when a recessive inheritance pattern is identified, a pathogenic variant in a heterozygous gene is less likely to be responsible for the observed symptoms. Conversely, if a likely pathogenic variant or a variant of uncertain significance is found in a homozygous state or exhibits a dominant inheritance mode, it is more likely to exert a significant impact on the individual's phenotype and disease symptoms.


Köhler et al (2021) The Human Phenotype Ontology in 2021, Nucleic Acids Research, Volume 49, Issue D1, 8 January 2021, Pages D1207–D1217, Mendelian Inheritance in Man, OMIM, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD)

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