prenatal screening for genetic disease carriers

39
Prenatal Screening for Genetic Disease Carrier Status Marie H. Beall, MD

Upload: others

Post on 12-Sep-2021

1 views

Category:

Documents


0 download

TRANSCRIPT

Page 1: Prenatal Screening for Genetic Disease Carriers

Prenatal Screening for Genetic Disease Carrier Status

Marie H. Beall, MD

Page 2: Prenatal Screening for Genetic Disease Carriers

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

Page 3: Prenatal Screening for Genetic Disease Carriers

Cystic Fibrosis cystic fibrosis transmembrane

conductance regulator (CFTR) Chloride ion channel Chromosome

7 q31.2

Page 4: Prenatal Screening for Genetic Disease Carriers

CF: symptoms Cough/shortness of breath

Due to excess mucous Bacterial colonization

Pancreas Pancreatitis Diabetes

Meconium ileus Absence of vas Death age 40 (av)

Page 5: Prenatal Screening for Genetic Disease Carriers

CF: Carrier ratesCaucasian 1/28

Ashkenazi 1/29

African American 1/60

Hispanic 1/48

Asian 1/90

Page 6: Prenatal Screening for Genetic Disease Carriers

CF: Detection rates25 mutations 45 mutations

Caucasian 88% 89%

Ashkenazi 94%

African American

64% 70%

Hispanic 72% 75%

Asian 49% 52%

Page 7: Prenatal Screening for Genetic Disease Carriers

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

Page 8: Prenatal Screening for Genetic Disease Carriers

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

Page 9: Prenatal Screening for Genetic Disease Carriers

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%

Page 10: Prenatal Screening for Genetic Disease Carriers

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

Page 11: Prenatal Screening for Genetic Disease Carriers

Canavan disease Leukodystrophy Aspartoacyclase deficiency

Breaks down N-acetyl-L-aspartic acid Chromosome 17 Loss of milestones, death by about age

4 Enlarged head

Page 12: Prenatal Screening for Genetic Disease Carriers

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

Page 13: Prenatal Screening for Genetic Disease Carriers

Fanconi anemia Defect in DNA repair Bone marrow failure High risk of leukemia Adults with other cancers Absent thumbs

Page 14: Prenatal Screening for Genetic Disease Carriers

Niemann-Pick Deficiency of sphingomyelinase Ataxia, dysarthria, dysphagia, dystonia For type A, life expectancy about 2

years

Page 15: Prenatal Screening for Genetic Disease Carriers

Bloom syndrome Defect in BLM, DNA helicase Short stature, facial

rash, cancer

Page 16: Prenatal Screening for Genetic Disease Carriers

Mucolipidosis IV Mutation of TRPML 1 (nonselective

cation channel) Lysosomal storage disorder Psychomotor retardation, absence of

the corpus callosum Developing blindness Slowly progressive

Page 17: Prenatal Screening for Genetic Disease Carriers

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

Page 18: Prenatal Screening for Genetic Disease Carriers

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

Page 19: Prenatal Screening for Genetic Disease Carriers

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

Page 20: Prenatal Screening for Genetic Disease Carriers

SMA Genetics

SMN2 gene produces a splice variant without exon 7

Page 21: Prenatal Screening for Genetic Disease Carriers

SMA Carrier testing Based on “dose” of exon 7 compared to

other parts of the SMN1 gene

Page 22: Prenatal Screening for Genetic Disease Carriers

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

Page 23: Prenatal Screening for Genetic Disease Carriers

SMA Recommendations ACMG (2008): Universal screening

recommended ACOG (2009): Universal screening not

recommended

Page 24: Prenatal Screening for Genetic Disease Carriers

“Fragile” X

Page 25: Prenatal Screening for Genetic Disease Carriers

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

Page 26: Prenatal Screening for Genetic Disease Carriers

Fragile X

Elongated face, large ears, large head

Macroorchidism Flat feet Hypotonia

Page 27: Prenatal Screening for Genetic Disease Carriers

Fragile X Males

1/1000 have premutation 1/3500-8900 have full mutation

Females 1/250-500 have premutation 1/4000 have full mutation

Page 28: Prenatal Screening for Genetic Disease Carriers

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)

Page 29: Prenatal Screening for Genetic Disease Carriers

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

Page 30: Prenatal Screening for Genetic Disease Carriers

Fragile X issues Diagnostic criteria not well defined Premutation carriers may be

symptomatic Premature ovarian failure Adult-onset ataxia

Page 31: Prenatal Screening for Genetic Disease Carriers

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

Page 32: Prenatal Screening for Genetic Disease Carriers

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”

Page 33: Prenatal Screening for Genetic Disease Carriers

Screening Alpha thalassemia

Southeast Asian Beta thalassemia

Southeast Asian, Mediterranean, Middle Eastern, Indian, African

Sickle cell, others African, Indian, SE Asian

Page 34: Prenatal Screening for Genetic Disease Carriers

Hemoglobin Alpha chains

4 copies Chromosome 16

Beta/delta/gamma chains Chromosome 11

Thalassemia = absence (usually) Others: S, C, E many others in beta

Page 35: Prenatal Screening for Genetic Disease Carriers

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

Page 36: Prenatal Screening for Genetic Disease Carriers

Beta Thalassemia Minor (or trait): mild anemia Major (Cooley’s anemia): severe

anemia, early death

Page 37: Prenatal Screening for Genetic Disease Carriers

Screening MCV (<80) Hgb electrophoresis

Quant A2 (>3.5% in beta) Hgb H (present in alpha)

Page 38: Prenatal Screening for Genetic Disease Carriers

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

Page 39: Prenatal Screening for Genetic Disease Carriers

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