Clinical Guidance

COL4A5 (XLAS)

Risk for ESKD

• Males. Large rearrangements and pathogenic nonsense and frameshift variants confer a 50% probability of ESKD before age 20 years .

In affected males with splice site variants, the probability of ESKD before age 30 years is around 65%, with 50% of males reaching ESKD by age 25 years . In individuals with splice variants, kidney prognosis differs significantly for those with truncating versus nontruncating variants at the transcript levels; ESKD occurs on average nine years earlier in those with truncating variants . Missense variants are associated with only a 30% probability of ESKD before age 30 years and a 50% probability of ESKD by age 40 years .

• Females. Both genotype and unbalanced X-chromosome inactivation pattern might affect the severity of kidney disease .

Source: GeneReviews — "Alport Syndrome"

Penetrance

The presence of COL4A3 or COL4A4 pathogenic variants is relatively common in the general population, with an overall prevalence of 0.94% according to gnomAD data, although this varies by ethnicity . The penetrance of ADAS is reduced. The severity of clinical manifestations varies greatly even within the same family; some heterozygotes may be asymptomatic, and some develop ESKD. The absolute risk of ESKD due to a heterozygous COL4A3 or COL4A4 pathogenic variant is estimated to be significantly lower than 3% .

Source: GeneReviews — "Alport Syndrome"

Diagnostic Criteria

Diagnostic criteria for Alport syndrome have been published .

Suggestive Findings

Molecular genetic testing for Alport syndrome should be considered in an individual with persistent glomerular hematuria, plus one or more of the following clinical findings, family history, pathology, or other findings .

Clinical findings

• Sensorineural deafness

• Anterior lenticonus and/or characteristic retinopathy

• Diffuse leiomyomatosis

Family history findings

• Hematuria

• Chronic kidney disease/ kidney failure

• Deafness associated with chronic kidney disease

Pathologic findings on kidney biopsy

• Negative or nonspecific routine immunofluorescence

• Type IV collagen abnormal expression

• Thin glomerular basement membranes

• Characteristic glomerular basement membrane thickening, lamellation, and scalloping

Source: GeneReviews — "Alport Syndrome"

Differential Diagnosis

Alport syndrome must be distinguished from other genetic disorders associated with persistent (6 months in duration) hematuria and/or combined nephritis and hearing loss . Of note, in a child with no known family history of hematuria, the most likely diagnoses are immunoglobin A nephropathy, Alport syndrome, and C3 glomerulopathy. Table 4. Genetic Disorders of Interest in the Differential Diagnosis of Alport Syndrome

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Alport syndrome, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 5. Alport Syndrome: Recommended Evaluations Following Initial Diagnosis

Source: GeneReviews — "Alport Syndrome"

Clinical Guidance

Dehydration should be avoided. Individuals who suffer recurrent corneal erosions may need to take measures (e.g., wearing goggles when riding a bicycle) to protect their corneas from minor trauma. Exposure to loud noise should be minimized.

Source: GeneReviews — "Alport Syndrome"

Therapies Under Investigation

A list of Alport syndrome clinical trials can be found at Alport Syndrome Foundation: Active Clinical Trials at a Glance. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "Alport Syndrome"

Surveillance Guidelines

Clinical practice recommendations for health surveillance of individuals with Alport syndrome have been published . These recommendations encourage early detection of microalbuminuria and proteinuria through regular surveillance. Table 7. Alport Syndrome: Recommended Surveillance

Source: GeneReviews — "Alport Syndrome"