Alport SyndromeGenetics and Diagnosis

Martin Gregory, MD, PhD

Professor of Medicine

University of Utah

Nothing to disclose

Modes of Inheritance

• X-linked (XLAS) – COL4A5 on chromosome Xq22 85% of cases

• Autosomal – COL4A3 or COL4A4 on chromosome 2q36-37– Recessive (ARAS) 10-15% of cases– Autosomal Dominant (ADAS) 1-5% of cases

• Diseases mimicking AS– MYH9 disorders: Epstein and Fechtner syndromes

Giant Platelets in Fechtner Syndrome

Autosomal Dominant AS

• Rare, mild• Vertical pattern

of inheritance• Male to male

transmission• Mutation in

COL4A3 or COL4A4

Autosomal Recessive AS

• Uncommon• Horizontal pattern

of inheritance• Consanguinity• Mutations in

COL4A3 or COL4A4

• Parents are “carriers”: they have TBMN

X-linked AS

• Most common• Vertical

pattern of inheritance

• NO male to male transmission

• Mutations in COL4A5

Implications of Inheritance Patterns

• Need to be as sure as possible of mode of inheritance before drawing conclusions or advising families.

• Prediction is treacherous, and genetic counseling subtle.

• Both the chance that children will inherit the disorder and the likely severity of the syndrome vary with the type of AS

Copyright ©2010 American Society of Nephrology

From the left of figure, Light weight solid line: large deletion, Dots: splice site mutation, Dash-Dot: small deletion, Heavy solid line: truncating mutation, Dash: missense mutation. Bekheirnia, M. R. et al. J Am Soc Nephrol 2010;21:876-883

Time to onset of ESRD associates with COL4A5 mutation type

Relevance of Specific Mutations in XLAS

• Large deletions and truncations cause the most severe phenotype.

• Splice-site mutations: intermediate severity• Missense mutations: relatively mild

disease.• In US, but not Europe, mutations in the

NC1 domain are more benign than those in the triple helical domain

Genetic Tests Available – COL4A5

• Sequencing and deletion analysis– Expensive. Sensitivity > 80% for XLAS

• Targeted mutation analysis (Carrier detection)– Cheap. Use this once family’s mutation is known.

• Test for 3 common “Adult types”– Cheap. Use if family has one of these 3 mutations.– ?use for screening certain groups

• Adults with dysmorphic hematuria and CKD.• Alport syndrome with late-onset renal failure

“Adult-type” Mutations in the USA – Known gene carriers

COL4A5 mutation

ESRD age in males

Male Female Total % of total

L1649R 39 150 222 372 48.6

C1564S 32 52 81 133 17.4

R1677Q 50 19 38 57 7.5

G1170S 38 13 11 24 3.1

c.2476delC 44 11 12 23 3.0

G1234X 42 7 16 23 3.0

16 others 70 63 133 17.4

Total 322 443 765 100Pont-Kingdon G et al. BMC Nephrology 2009; 10:38

Genetic Tests Available – COL4A3/4

• COL4A3 and COL4A4 sequencing and deletion analysis– Expensive. Sensitivity >80%

• Use after COL4A5 mutation excluded or if inheritance suggests autosomal transmission

• Can use to diagnose ~40% of cases of TBMN

Before Genetic Testing

•Gather a complete family history, patient history, u/a.•Make your best guess for mode of inheritance•Is a mutation known in the family?•Is genetic testing appropriate?

•Families making reproductive decisions•To avoid kidney biopsy, or if diagnostic certainly is desired

Choice of an Appropriate Genetic Test

•Targeted analysis or Adult-type 3 mutation test if the mutation is known in the family•If no mutation is known, usually start with sequencing, including deletion analysis in females•May start with Adult-type 3 mutation test in families with renal failure in middle age•COL4A3/4 sequencing if autosomal disease likely or if COL4A5 testing was negative

Now you Tell me …

A lab test has 90% sensitivity and 99% specificity. The disease it tests for occurs in 1 in 50,000 people. A person in the population has a positive test. What is the likelihood that he has the disease tested for?

99%90%50%10%<1%

Now you Tell me …

A lab test has 90% sensitivity and 99% specificity. The disease it tests for occurs in 1 in 50,000 people. A person in the population has a positive test. What is the likelihood that he has the disease tested for?

99%90%50%10%<1%

Of people with the disease 90% will have a positive testOf people without the disease, 1% will have a positive test

Now you Tell me …

A lab test has 90% sensitivity and 99% specificity. The disease it tests for occurs in 1 in 50,000 people. A person in the population has a positive test. What is the likelihood that he has the disease tested for?

Test 100,000 people1.8 true positives

99%90%50%10%<1%

Now you Tell me …

A lab test has 90% sensitivity and 99% specificity. The disease it tests for occurs in 1 in 50,000 people. A person in the population has a positive test. What is the likelihood that he has the disease tested for?

Test 100,000 people1.8 true positives1,000 false positives

Probability of disease 2/1002 = 0.2%

99%90%50%10%<1%

Now you Tell me …

A lab test has 90% sensitivity and 99% specificity. The disease it tests for occurs in 1 in 50,000 people. A person in the population has a positive test. What is the likelihood that he has the disease tested for?

Test 100,000 people1.8 true positives1,000 false positives

Probability of disease

2/1002 = 0.2%

99%90%50%10%<1%

A priori probability A posteriori

Now you Tell me …

A lab test has 90% sensitivity and 99% specificity. The disease it tests for occurs in 1 in 50,000 people. A person in the population has a positive test. What is the likelihood that he has the disease tested for?

Test 100,000 people1.8 true positives1,000 false positives

Probability of disease 2/1002 = 0.2%

99%90%50%10%<1%

A priori probability A posteriori

if test is +

0.002%50%98%

0.2%98%99.998%

Conclusions about Genetic Testing•If a family has several males with ESRD, genetic testing will likely not improve prognostic accuracy.•If the family is very small, the phenotype is likely severe.•Before giving advice that may affect reproductive decisions, consider getting a genetic diagnosis for the prospective parent(s) involved (not just a diagnosis in the family).•Only get a genetic diagnosis if it can change what you will do.•Even very good tests may be misleading if misapplied