Alport Syndrome Panel, Sequencing and Deletion/Duplication

  • Recommended test to confirm carrier status or a diagnosis of AS or MYH9-related disease.
  • Regions of low coverage and reported variants are confirmed by Sanger sequencing as necessary.
  • Recommended test for a sequence variant previously identified in a family member.
  • A copy of the family member’s test result is required.
  • Recommended test for a large deletion/duplication previously identified in a family member.
  • A copy of the family member’s test result is recommended.

Alport syndrome (AS) is a spectrum of disorders that may range from isolated nonprogressive microscopic hematuria and proteinuria to progressive renal insufficiency, end stage renal disease (ESRD), eye findings, and sensorineural hearing loss (SNHL). The three main genes causative for AS (COL4A3, COL4A4, and COL4A5) are critical to the collagen IV a345 network of basement membranes. Pathogenic variants in COL4A5, causative for approximately 80-85% of AS, are inherited in an X-linked recessive (XLR) manner. Approximately 15-20% of AS is autosomal dominant (AD) or autosomal recessive (AR) due to pathogenic variants in the COL4A3 or COL4A4 genes.

Disease Overview

Symptoms

Symptoms of AS and Related Disorders
Symptom Categories X-Linked and Autosomal Recessive AS Autosomal Dominant AS MYH9-Related Disease

Renal symptoms

Renal disease progressing from microhematuria and proteinuria to renal insufficiency and ESRD

  • Males with X-linked AS: 60% have ESRD by age 30 and 90% by age 40
  • Females with X-linked AS: 12% have ESRD by age 40, 30% by age 60, and 40% by age 80
  • Individuals with autosomal recessive AS: most develop ESRD by age 30

Slowly progressive renal insufficiency presenting later in life

Early adult onset of renal disease, initially presenting as glomerular nephropathy

Hearing loss

Progressive SNHL in late childhood

Slowly progressive SNHL later in life

SNHL

Ocular issues

Anterior lenticonus

  • Presents in second or third decade of life
  • Observed in ~13% of males with X-linked AS
  • Associated with certain COL4A5 variants

Maculopathy

  • Defined by whitish yellow flecks in the perimacular region
  • Observed in 14% of males with X-linked AS

Corneal endothelial vesicles or corneal erosion in X-linked AS

Posterior subcapsular cataracts in X-linked AS

Ocular lesions are uncommon

Cataracts

Other

Diffuse leiomyomatosis (benign smooth muscle cell proliferation) of the esophagus and tracheobronchial tree may occur in X-linked AS

Thoracic and abdominal aortic aneurysms in a few males with X-linked AS at <40 years

Congenital presentation of large platelets and thrombocytopenia

Adult onset of elevated liver enzymes

Etiology of Alport Syndrome

AS is caused by pathogenic variants in collagen genes that contribute to the collagen IV network of basement membranes.

Penetrance of Alport Syndrome and MYH9-Related Disease

  • Complete for males with X-linked AS and both males and females with AR COL4A3 and COL4A4 variants and MYH9-related disease
  • Possible incomplete penetrance for AD COL4A3 and COL4A4 variants

Prevalence of Alport Syndrome

  • 1/50,000 births 
  • 0.2% of U.S. adults and 3% of children with ESRD have AS 

Inheritance

  • COL4A5: XLR
  • COL4A3 and COL4A4: AD and AR, depending on the variant
  • MYH9: AD

Genotype-Phenotype Correlation

  • Large COL4A5 rearrangements, nonsense, frameshift, and splice site variants are associated with a 50% risk for ESRD by age 20, 90% risk of ESRD by age 30, and a 50% risk for SNHL by age 10.
  • Pathogenic missense COL4A5 variants confer a 50% risk for ESRD by age 30 and 50% risk of SNHL by age 20.
  • Leiomyomatosis only occurs in individuals with a deletion of both COL4A5 and COL4A6 when the COL4A6 breakpoint is in the second intron of the gene.

Test Interpretation

Clinical Sensitivity

  • ~97-100% for AS - 
  • 98% for MYH9-related disease 

Analytical Sensitivity

For massively parallel sequencing:

Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

99.9

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

99.9

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

Limitations

  • A negative result does not exclude a diagnosis of AS or MYH9-related disease.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of targeted genes
    • Regulatory region and deep intronic variants
    • Breakpoints of large deletions/duplications
    • Deletions/duplications in COL4A3, COL4A4, and MYH9 genes
    • Noncoding transcripts
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants
    • Single exon deletions/duplications in the following exons:
      • COL4A5 (NM_000495) 8, 25, 40, 42, 43

Genes Tested

Gene Symbol MIM # Disorders Inheritance

COL4A3

120070

Alport syndrome 2

Alport syndrome 3

Hematuria, benign familial

AR/AD

COL4A4

120131

Alport syndrome 2

Hematuria, familial benign

AR/AD

COL4A5

303630

Alport syndrome 1, X-linked

XLR

MYH9

160775

Deafness 17

Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

AD

References

Additional Resources