Alport Syndrome

Genetics 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
 Time to onset of ESRD associates with COL4A5 mutation type

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

Copyright ©2010 American Society of Nephrology

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 ESRD age Male Female Total % of total
mutation in males
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 322 443 765 100
Pont-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 …
Of people with the
A lab test has 90% sensitivity and disease 90% will
99% specificity. The disease it tests have a positive test
for occurs in 1 in 50,000 people. A Of people without
person in the population has a the disease, 1%
positive test. What is the likelihood will have a positive
that he has the disease tested for? test

99%
90%
50%
10%
<1%
 Now you Tell me …
Test 100,000 people
A lab test has 90% sensitivity and 1.8 true positives
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 …
Test 100,000 people
A lab test has 90% sensitivity and 1.8 true positives
99% specificity. The disease it tests 1,000 false positives
for occurs in 1 in 50,000 people. A
person in the population has a Probability of disease
positive test. What is the likelihood 2/1002 = 0.2%
that he has the disease tested for?

99%
90%
50%
10%
<1%
 Now you Tell me …
Test 100,000 people
A lab test has 90% sensitivity and 1.8 true positives
99% specificity. The disease it tests 1,000 false positives
for occurs in 1 in 50,000 people. A
person in the population has a Probability of disease
positive test. What is the likelihood
2/1002 = 0.2%
that he has the disease tested for?

99% A priori probability A posteriori

90%
50%
10%
<1%
 Now you Tell me …
Test 100,000 people
A lab test has 90% sensitivity and 1.8 true positives
99% specificity. The disease it tests 1,000 false positives
for occurs in 1 in 50,000 people. A
person in the population has a Probability of disease
positive test. What is the likelihood 2/1002 = 0.2%
that he has the disease tested for?

99% A priori probability A posteriori

90% if test is +
50%
10% 0.002% 0.2%
<1% 50% 98%
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