Alport syndrome (ATS) is a rare disease caused by genetic pathogenic variants in one of the type IV collagen genes that encode connective tissue proteins localized within basement membranes of the kidneys, ears and eyes. Thus, the disease is characterized by renal, cochlear, and ocular involvement1, 2. Pathogenic variants in COL4A3, COL4A4, or COL4A5 result in a spectrum of phenotypes, from Alport syndrome to thin basement membrane nephropathy (TBMN), including X-linked Alport syndrome (XLAS), autosomal recessive Alport syndrome (ARAS), or autosomal dominant collagen IV disorders (ADAS and TBMN) 3, 4, 5.
X-linked, autosomal recessive, autosomal dominant
1/50,000 1, 2.
Most characteristic clinical features of Alport syndrome include the following1,2:
- Hematuria (blood in urine)
- Hypertension, followed by edema and nephrotic syndrome
- Renal insufficiency
Hearing impairment and cochlear findings:
- Bilateral high-frequency sensorineural hearing loss
- Progression of hearing loss to complete deafness
- Anterior lenticonus
- Perimacular flecks
As should be considered in individuals with the following features:
- Renal: Hematuria, proteinuria and renal insufficiency in older individuals
- Cochlear: Bilateral high-frequency sensorineural hearing loss (SNHL) with onset in late childhood or early adolescence.
- Ocular: Anterior lenticonus is a characteristic feature and perimacular flecks can also be present
- Family history: positive for individuals with above symptoms
- Diagnosis of Alport syndrome is confirmed by the identification of a pathogenic variant in one of the following genes: COL4A3, COL4A4, COL4A5.
There is no cure for Alport syndrome but treatment can relieve symptoms 1, 2.
- Angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker in proteinuric individuals
- Routine treatment of hypertension
- Renal transplantation for ESRD
- Routine treatment of SNHL and cataracts
- Surgical intervention for symptomatic leiomyomas.
- Acute poststreptococcal glomerulonephritis
- Medullary cystic disease
- Polycystic kidney disease
- Multicystic renal dysplasia
- Nail-Patella syndrome
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for Alport syndrome using NGS Panel Genomic:
Step 1: Whole genome sequencing from a single filter card (drop of blood), covering the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Alport syndrome panel. Copy Number Variants analysis derived from NGS data is also included.
Step 2: If no pathogenic variant is identified in Step1, continue with bioinformatics analysis covering genes that are either implicated or associated with overlapping phenotype or similar pathways.
- Individuals with a positive family history of Alport syndrome.
- Individuals with symptoms suggestive of Alport syndrome (regardless of family history).
Confirmation of a clinical diagnosis through genetic testing of Alport syndrome can allow for genetic counseling and may direct medical management.
Overview of the genes in CENTOGENE´s Alport syndrome panel:
|Gene||OMIM||Chromosomal locus||Inheritance||Frequency of pathogenic variants||Associated and allelic disorders|
|2q36.3||Autosomal dominant, Autosomal recessive||15-20% 3, 4, 6||Alport syndrome, autosomal dominant (104200); Alport syndrome, autosomal recessive (203780): Hematuria, benign familial (141200)|
|COL4A4||120131||2q36.3||Autosomal dominant, Autosomal recessive||15-20% 3, 4, 6||Alport syndrome, autosomal dominant (104200); Alport syndrome, autosomal recessive (203780): Hematuria, benign familial (141200)|
|COL4A5||303630||Xq22.3||X-linked||65% 3, 4, 6||Alport syndrome X-linked (301050)|