Transcript Genetics Overview - Alport Syndrome Foundation

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
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
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 …
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 test
Of 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?
99%
90%
50%
10%
<1%
Test 100,000 people
1.8 true positives
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%
90%
50%
10%
<1%
A priori probability A posteriori
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%
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