The patient's journey with a v-ATPase disorder usually starts (or better said it's acknowledged) when a person receives a genetic report with a positive result for a v-ATPase gene. But there is quite a lot of information in these reports and understanding them can be both crucial and complex for families navigating this diagnosis. Besides the positive or negative result, these tests offer insights into the molecular underpinnings of a patient's condition. However, deciphering them requires more than just a basic understanding of biology.

We will explore the components of a genetic report, understanding its contents to empower patients and their families with the knowledge they need to navigate their journey with a v-ATPase disorder.

Unfortunately, v-ATPase associated genes are not yet included in common genetic panels or newborn screening tests for faster diagnosis, and therefore more sophisticated analysis are needed in order to detect these genetic alterations. Thus, typically one finds a v-ATPase diagnosis after performing a whole exome sequencing (WES) analysis. 

WES  is a powerful genetic test used to analyze all the regions of the DNA in an individual's genome that code for functional proteins in the cells - known as the exome - where most of the disease-causing variants exist. 

Whole exome sequencing may provide several types of genetic information, including:

• Single nucleotide variants (SNVs): Point mutations involving the substitution of one nucleotide for another within the coding region of a gene.
• Insertions and deletions (indels): Small insertions or deletions of DNA within coding regions, which may disrupt gene function.
• Splice site variants: Mutations that affect the junctions between exons and introns, which can alter mRNA splicing and gene expression.
• Copy number variants (CNVs): Large-scale duplications or deletions of genomic segments, including exonic regions, which can lead to gene dosage imbalances and disease.

Although the format or language of the report may differ slightly, typically a genetic report will contain the following information exemplified here for a SNV:

Let's dive into the components of this report and explore the different possibilities.

Gene identifies the v-ATPase gene affected.

Coding DNA and Variant report the alterations that occurred at the DNA and Protein levels respectively. These alterations are typically represented using a standardized format known as the Human Genome Variation Society (HGVS) nomenclature, and common possibilities for variant representation include:

• Substitution (SNV):  
  • c.448 C>T: A substitution of cytosin (C) with thymine (T) at nucleotide position 488 in the coding DNA sequence.
  • p.L150F: Amino acid change from leucine (L/Leu) to phenylalanine (F/Phe) at position 150 of the protein.

• Insertion (INS):  
  • c.456_457insT: Insertion of a thymine (T) nucleotide between positions 456 and 457 in the coding DNA sequence.
  • p.Glu78_Thr79insPro: Insertion of proline (Pro) between amino acid positions 78 and 79 of the protein.

• Deletion (DEL):  
  • c.789_792delAGTC: Deletion of the AGTC nucleotides between positions 789 and 792 in the coding DNA sequence.
  • p.Lys102del: Deletion of lysine (Lys) at position102 of the protein.

• Duplication (DUP):  
  • c.234_237dupATCG:Duplication of the ATCG nucleotides between positions 234 and 237 in the coding DNA sequence.
  • p.Ala56dup:Duplication of alanine (Ala) at position 56 of the protein.

• Frameshift Variant:  
  • c.345_346insG: Insertion of a guanine (G) nucleotide between positions 345 and 346, causing a frameshift mutation.
  • p.Pro78fs: Frameshift mutation resulting in a premature stop codon after position 78 of the protein.

• Splice Site Variant:  
  • c.678+1G>T: Mutation at the +1 position of intron 678, affecting the canonical splice donor site.
  • c.123-2A>G: Mutation at the -2 position of intron 123, affecting the canonical splice acceptor site.

• Large Rearrangements  
  • c.123_456dup: Duplication of a large segment of DNA spanning from nucleotide position 123 to 456 in the coding DNA sequence.
  • c.789_890del: Deletion of a large segment of DNA spanning from nucleotide position 789 to 890 in the coding DNA sequence.

Zygosity refers to the genetic composition of an individual with respect to a specific genetic variant. 

Typically varies between "Heterozygous" when one allele carries a variant, while the other allele is wild-type; "Compound heterozygous" when two different variants or mutations are present on each allele; "Homozygous" when both alleles carry the same variant or mutation; and "Hemizygous" when only one gene copy is present due to deletion or absence of the other copy. 

Mode of Inheritance refers to the pattern in which a genetic condition is passed down from one generation to the next within a family. The possibilities for mode of inheritance typically include:

• Autosomal dominant when the genetic condition is caused by a mutation in one copy of a gene.
• Autosomal recessive when the genetic condition is only caused when mutations exist in both copies of a gene.
• X-linked dominant when the genetic condition is caused by a mutation in a gene located on the X chromosome, and it typically affects both males and females.
• X-linked recessive when the genetic condition is caused by a mutation in a gene located on the X chromosome, and it typically affects males more severely. Affected males inherit the mutated gene from their mothers, who are typically carriers but do not show symptoms.
• Y-linked when the genetic condition is caused by a mutation in a gene located on the Y chromosome.   

Inherited from indicates the origin of a genetic variant or mutation observed in an individual. It may have maternal or paternal inheritance or the variant might be de novo (new mutation), indicating that the variant arose spontaneously in the individual and is not inherited from either parent, which is the most common in v-ATPase genetic disorders.

Classification categorizes the genetic variants based on their potential impact on protein function and association with disease. A genetic variant may be classified as "Pathogenic" when the variant is known or predicted to cause disease or dysfunction based on strong evidence from functional studies, population data, or clinical observations; "Likely Pathogenic" when the variant is likely to cause disease or dysfunction based on available evidence but requires further validation or clinical correlation to confirm its pathogenicity; "Benign" when the variant is unlikely to cause disease or dysfunction and is considered part of normal genetic variation within the population; "Likely Benign" when the variant is likely to be benign based on available evidence but requires further validation or clinical correlation to confirm its benign nature; or "Variant of Uncertain Significance" when the variant has unclear significance, meaning its impact on protein function and association with disease is uncertain - VUSs require further investigation, functional studies, or additional evidence to determine their clinical significance. 

In addition to Whole Exome Sequencing (WES), v-ATPase disorders can also be identified with Whole Genome Sequencing (WGS) tests, which cover the entire DNA sequence inclusive of the DNA coding region covered in a WES test. The report and nomenclature in a WGS test are comparable to a WES. 

In cases where a v-ATPase genetic alteration occurs due to large insertions or deletions in specific chromosomal regions encompassing v-ATPase genes, a diagnosis may also be obtained by performing a Whole Genome Chromosomal Microarray, also known as Chromosomal Microarray Analysis (CMA). This is a high-resolution genetic test used to detect abnormalities in the chromosomes' structure allowing for the detection of gains, losses, or rearrangements of chromosomal segments in the genome.

Understanding your genetic report can empower you and your family with tools to navigate your v-ATPase disorder journey more effectively, fostering informed decision-making and personalized care.      

We are collaborating with Probably Genetic as a patient-finding partner for our community. If you or anyone you know is looking for a genetic testing, Probably Genetic runs a no-cost, low barrier testing program for individuals experiencing seizures, developmental delay-related disorders or any other v-ATPase related symptoms. Probably Genetic is operating only in the U.S. at the moment, but we will keep you updated once we find a partner worldwide.

You can read more about what v-ATPase is, its function and regulation here and find out more about what symptoms and diseases are a result of v-ATPase failure here.