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Glycogen Storage Disease
Type IV/ Adult Polyglucosan
Body Disease Carrier
Screening
Ruth Kornreich, Ph.D.
Jewish genetic diseases
• 1970’s & 1980’s: Ashkenazi Jewish genetic diseases
were recognized as a major problem to be addressed
• 2000: Dr. Michael Kaback, “United States and
Canada, the incidence of TSD in the Jewish population
had declined by more than 90%”
RECOMMENDED ASHKENAZI JEWISH (AJ) CARRIER SCREENING
Disease
Pan-ethnic Diseases
Cystic fibrosis (CF)
Recommendation
ACMG ACOG
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AJ Carrier
Frequency
1 in 23
1 in 134
Fragile X syndrome (FX)
Spinal muscular atrophy (SMA)
AJ Diseases
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1 in 41
Bloom syndrome (BS)
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1 in 134
Canavan disease (CD)
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1 in 55
Familial dysautonomia (FD)
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1 in 31
Fanconi anemia group C (FA)
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1 in 100
Gaucher disease (GD)
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1 in 15
Mucolipidosis IV (MLIV)
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1 in 89
Niemann-Pick disease type A (NPD-A)
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1 in 115
Tay-Sachs disease (TSD)
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1 in 27
ADDITIONAL SCREENING OPTIONS
Additional AJ Diseases
Familial hyperinsulinism
Glycogen storage disease Ia
Joubert syndrome 2
Lipoamide dehydrogenase deficiency
Maple syrup urine disease Ib
Nemaline myopathy
Usher syndrome type IF
Usher syndrome type III
Walker-Warburg syndrome
Abetalipoproteinemia
Galactosemia
Hermansky-Pudlak syndrome
LDLR-Hypercholesterolemia
Additional
AJ Panel
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Smith-Lemli-Opitz syndrome
Tyrosinemia type 1
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Wilson disease
Zellweger syndrome
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Expanded
Pan-Ethnic Panel
AJ Carrier
Frequency
1 in 68
1 in 64
1 in 110
1 in 107
1 in 97
1 in 168
1 in 147
1 in 120
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1 in 90
1 in 131
1 in 120
1 in 235
1 in 67
1 in 100
1 in 100
1 in 100
1 in 110
Expanded Carrier Screening: Standard of Care
Expanded Carrier Screening: Standard of Care
▶
ACMG
Five criteria should be met for a disorder to
be included on a panel:
–
Most at risk patients would consider
having prenatal diagnosis to facilitate
reproductive decision making
–
Patients must provide consent to screen
for adult-onset disorders (especially where
there may be implications for the individual
or their family members)
–
For each condition, the causative genes,
mutations, and mutation frequencies
should be known in the population being
tested so that residual risk for those that
test negative can be correctly assessed
–
Validated clinical association between the
mutations detected and the severity of the
disorder
–
Compliance with the ACMG Standards and
Guidelines for Clinical Genetics
Laboratories
Technologies used for Carrier Screening
Genotyping versus Sequencing
▶
Historically carrier
screening was limited to
genotyping.
– Relatively Cheap
– Relatively Fast
– Straightforward “carrier” or
“non-carrier” for
predefined set of
mutations
▶
Historically full gene sequencing
was reserved for diagnostic
purposes.
–
Expensive
–
Time Consuming
–
Could reveal confusing results
Expanded Carrier Screening in Reproductive Medicine
A Joint Statement of the American College of Medical Genetics and Genomics, American
College of Obstetricians and Gynecologists, National Society of Genetic Counselors,
Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine
INTERPRETATION OF MOLECULAR FINDINGS
▶
The genes and variants included should have a well-understood relationship with a
phenotype. Phenotype–genotype correlation should at a minimum include multiple
families that provide a minimum level of unbiased ascertainment. Laboratories should
be able to provide information about the phenotype for any conditions included on a
panel.
▶
When the carrier frequency and detection rate are both known, residual risk
estimation should be provided in laboratory reports. Where this information is not
available or reliable, the limitations of interpretation of negative screening should be
clearly communicated in laboratory reports.
▶
Because all individuals have numerous variants within their genes, restricting the
variants that are included in screening to those with the highest likelihood of being
pathogenic will decrease the number of people who require follow-up. Variants of
uncertain significance detected by sequencing should not be reported
▶
The laboratory performing screening should report all variants that are pathogenic or
likely pathogenic.
8
MGTL carrier screening expansion philosophy
Disease selection criteria
1. Early-onset, severe
2. Childhood or early adult onset and progressive
3. Early detection for prevention of catastrophic events
or for better lifetime disease management
Ashkenazi Jewish carrier screening
(expansion #1):
18 new diseases
Ashkenazi Jewish Carrier Screening
(expansion to sequencing #2): 20 new diseases
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Choreoacanthocytosis VPS13A
17.
Deafness, Autosomal Recessive 77 LOXHD1 18.
(1/180)
Enhanced S-Cone Syndrome NR2E3
19.
Factor XI Deficiency F11 (1/11)
20.
Familial Hypercholesterolemia LDLR (1/69)
Glycogen Storage Disease, Type IV / Adult
Polyglucosan Body Disease GBE1 (1/68)
Glycogen Storage Disease, Type VII PFKM
(1/250)
Hermansky-Pudlak Syndrome, Type 3 HPS3
(1/235)
Mitochondrial Complex I Deficiency NDUFAF5
(1/290)
Non-Syndromic Hearing Loss (GJB2-Related)
GJB2 (1/21)
Osteopetrosis 1 TCIRG1 (1/350)
Pontocerebellar Hypoplasia, Type 1A VRK1
(1/225)
Primary Ciliary Dyskinesia DNAH5 (1/174)
Primary Ciliary Dyskinesia DNAI1 (1/352)
Primary Ciliary Dyskinesia DNAI2 (1/200)
Primary Hyperoxaluria, Type 3 HOGA1
Familial Mediterranean Fever MEFV (1/13)
Glycogen Storage Disease, Type II GAA
(1/58)
Phenylalanine Hydroxylase Deficiency PAH
(1/225)
Retinitis Pigmentosa 28 FAM161A (1/214)
8 out of 10 Ashkenazi
Jewish individuals tested
for 58 disorders will
screen positive
Carrier Frequency of GBE1 Pathogenic and Likely
Pathogenic Variants Obtained During Screening of
2775 Ashkenazi Jewish Individuals
Variant
n
p.Y329S
38
IVS15+5289delins
16
p.Y329C
2
p.Y535C
1
p.G299X
1
Overall carrier frequency of 1 in 48 (58/2775)
Carrier Frequency of GBE1 Pathogenic and Likely
Pathogenic Variants Obtained During Screening of
21319 Individuals
Variant
n
p.Y329S
63
IVS15+5289delins
29
p.Y329C
53
c.691+2T>C
32
15 Other variants (n=1-3)
20
Overall carrier frequency of 1 in 108 (197/21319)