prenatal screening for genetic disease carriers

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