prenatal screening for genetic disease carriers
TRANSCRIPT
Prenatal Screening for Genetic Disease Carrier Status
Marie H. Beall, MD
Current Recommendations Cystic fibrosis Screening for Ashkenazi descent
Tay Sachs disease Canavan disease Familial dysautonomia
Spinal Muscular atrophy Fragile X Alpha thalassemia Beta thalassemia Sickle cell anemia
Cystic Fibrosis cystic fibrosis transmembrane
conductance regulator (CFTR) Chloride ion channel Chromosome
7 q31.2
CF: symptoms Cough/shortness of breath
Due to excess mucous Bacterial colonization
Pancreas Pancreatitis Diabetes
Meconium ileus Absence of vas Death age 40 (av)
CF: Carrier ratesCaucasian 1/28
Ashkenazi 1/29
African American 1/60
Hispanic 1/48
Asian 1/90
CF: Detection rates25 mutations 45 mutations
Caucasian 88% 89%
Ashkenazi 94%
African American
64% 70%
Hispanic 72% 75%
Asian 49% 52%
Current Recommendations ACMG (2004):
Test all pregnant couples (NIH) Panel of 23 mutations
Remove two of the original 25 May modify for local ethnicities
ACOG (2011) Agrees with above
Testing for Ashkenazi ethnicity ACOG (2009): Tay-Sachs, Canavan,
Cystic fibrosis, Familial dysautonomia ACMG (2008): add Fanconi anemia,
Niemann-Pick, Bloom syndrome, Mucolipidosis IV, Gaucher disease
Carrier RatesCystic fibrosis 1/29 95%
Tay Sachs disease 1/31 92-99%Canavan disease 1/41 97%Familial dysautonomia 1/31 99%Fanconi anemia gpC 1/89 99%Niemann-Pick type A 1/90 97%Bloom syndrome 1/107 99%Mucolipidosis IV 1/127 95%Gaucher disease type 1 1/18 89-95%
Tay-Sachs Disease Hexoaminidase A deficiency
HEXA resides in lysosomes, breaks down GM2 ganglioside
Chromosome 15 Usual course: normal development until
about 6 mos, then relentless deterioration, death by about 4 yrs
Canavan disease Leukodystrophy Aspartoacyclase deficiency
Breaks down N-acetyl-L-aspartic acid Chromosome 17 Loss of milestones, death by about age
4 Enlarged head
Familial dysautonomia Disorder of sensory and autonomic
nervous system Absent IKAP chromosome 9 Difficulties with swallowing, vomiting,
absence of tears, abnormal gait, abnormal heat, cold, pain perception
Death by about 30
Fanconi anemia Defect in DNA repair Bone marrow failure High risk of leukemia Adults with other cancers Absent thumbs
Niemann-Pick Deficiency of sphingomyelinase Ataxia, dysarthria, dysphagia, dystonia For type A, life expectancy about 2
years
Bloom syndrome Defect in BLM, DNA helicase Short stature, facial
rash, cancer
Mucolipidosis IV Mutation of TRPML 1 (nonselective
cation channel) Lysosomal storage disorder Psychomotor retardation, absence of
the corpus callosum Developing blindness Slowly progressive
Gaucher Disease Deficiency of glucocerebrosidase Lysosomal storage disorder Enlargement of liver and spleen Bone pain Brain not involved Treatment available: enzyme
replacement or bone marrow transplant
Spinal Muscular Atrophy Autosomal recessive degeneration of motor
neurons with muscle weakness Type 1 (Werdnig-Hoffman): Severe
weakness at birth or by 3 months, death by 2 years There are three types
Absence of SMN gene in most cases No correlation of mutation and severity of disease
SMA prevalence Second most common lethal AR
disorder (after CF) Carrier rates 1/40-1/60 Gene is survival motor neuron (SMN)
found on 5q13 Two genes exist SMN1 responsible for disease
SMA Genetics
SMN2 gene produces a splice variant without exon 7
SMA Carrier testing Based on “dose” of exon 7 compared to
other parts of the SMN1 gene
SMA testing issues High mutation rate in gene
2% of cases are de novo 5% of population has 3 copies of SMN1
Some carriers have 2 genes in cis Difficult to estimate disease severity
SMA Recommendations ACMG (2008): Universal screening
recommended ACOG (2009): Universal screening not
recommended
“Fragile” X
Fragile X manifestations Full mutation (males>females)
Autistic behaviors Moderate to severe MR Seizures Physical features
Premutation Premature ovarian failure Tremor/ataxia Possible subtle neurocognitive
Fragile X
Elongated face, large ears, large head
Macroorchidism Flat feet Hypotonia
Fragile X Males
1/1000 have premutation 1/3500-8900 have full mutation
Females 1/250-500 have premutation 1/4000 have full mutation
Fragile X genetics Caused by expansion of CGG repeat
Associated with non-expression of FMR1 Categories of CGG repeats
Normal (average 29-31) Gray zone (40-60) Premutation (55-200) Full mutation (> 200 repeats)
Maternal repeats Percent risk of expansion to full mutation (>200 repeats)
55-59 0-1360-69 5-2170-79 17-5880-89 50-7390-99 80-100100-200 75-99
Fragile X issues Diagnostic criteria not well defined Premutation carriers may be
symptomatic Premature ovarian failure Adult-onset ataxia
Fragile X recommendations ACMG (2005): Universal carrier testing
not recommended ACOG (2010): Carrier screening for
indications only Family history Early ovarian failure Late tremor/ataxia
Hemoglobinoathies ACOG (2007): “Individuals of African,
Southeast Asian, and Mediterranean ancestry are at a higher risk for being carriers of hemoglobinopathies and should be offered carrier screening”
Screening Alpha thalassemia
Southeast Asian Beta thalassemia
Southeast Asian, Mediterranean, Middle Eastern, Indian, African
Sickle cell, others African, Indian, SE Asian
Hemoglobin Alpha chains
4 copies Chromosome 16
Beta/delta/gamma chains Chromosome 11
Thalassemia = absence (usually) Others: S, C, E many others in beta
Alpha Thalassemia Silent carrier: absence of one alpha chain
Silent carrier Trait: absence of two alpha chains
SE Asians more likely cis Mild anemia/lower MCV
Hgb H disease Anemia, hemolysis
Hydrops fetalis
Beta Thalassemia Minor (or trait): mild anemia Major (Cooley’s anemia): severe
anemia, early death
Screening MCV (<80) Hgb electrophoresis
Quant A2 (>3.5% in beta) Hgb H (present in alpha)
Carrier rates Alpha thal: 5% of Chinese in BC Beta thal: 9% of Egyptian children Sickle cell: 8% of African Americans
Overall 1/20 to 1/11
Conclusions You: Know national
recommendations Know your patients Document that tests
were offered Be ready to answer
questions
Policy: Keep track of test
results Keep track of
uncertain/unknown results
Reasonable expectations regarding counseling