Chromosome breakage disorders

Question 1

ATAXIA-TELANGIECTASIA
Responsible gene:
Protein:
Cytogenetic locus:
Inheritance: carriers risk?
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:

Answer 1

Responsible gene: ATM
Protein: Serine-protein kinase ATM
Cytogenetic locus: 11q22.3
Inheritance: AR (carriers may be at risk for cancer)
Clinical Features and Diagnostic Criteria: Progressive cerebellar ataxia (onset age 1-4y), oculomotor apraxia, conjunctival telangiectasia, immunodef, choreoathetosis, ionizing radiation sensitivity, risk cancer (lymphoma and leukemia)
Clinical Tests: AFP, decreased ATM kinase activity, 7;14 translocation (5-15% of lymphocytes after PHA stimulation)
Molecular Tests:ATM sequencing (>95%). Amish founder mutation
Disease Mechanism: Most mutations are null leading to no protein product. The normal protein finds double strand dsDNA breaks and coordinates cell cycle checkpoints prior to repair
Treatment/Prognosis: IVIG if immunodeficient, PT to reduce contractures, wheelchair usually by age 10, supportive therapy for drooling, choreoathetosis, and ataxia. Avoid ionizing radiation. Regular medical visits to monitor for S/Sxof malignancy

Question 2

BLOOMSYNDROME
Responsible gene:
Protein:
Cytogenetic locus:
Inheritance:
Clinical Features and Diagnostic Criteria: cancer risk?
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:

Answer 2

Responsible gene: BLM
Protein: Bloom syndrome protein
Cytogenetic locus: 15q26.1
Inheritance: AR (1/100 carrier freqin Ashkenazi Jewish)
Clinical Features and Diagnostic Criteria: IUGR, hyper and hypopigmentation, butterfly distribution sun sensitive telangiectasia, microcephaly, high pitched voice, normal intelligence, immunodeficiency, azoospermia, POF, increased risk of cancer (wide distribution of type and site (colon most common), often multiple primary tumors).
Clinical Tests: Chromatid/chromosome breaks; triradial and quadriradialfigures
Molecular Tests:BLM 2881 del6ins7 (97% mutant allele in AJ)
Disease Mechanism: Abnormal DNA replication and repair leading to genomic instability.
Treatment/Prognosis: Increased cancer surveillance, decrease exposure to UV light and x-ray, BMT, colon cancer surveillance

Question 3

FANCONI ANEMIA
Responsible genes(Protein and Cytogenetic locus):
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:

Answer 3

Responsible genes(Protein and Cytogenetic locus): FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG (Fanconianemia group A, B, C, D2, E, F, and G protein; 16q24.3, Xp22.3, 9q22.3, 3p25.3, 6p22-21, 11p15, and 9p13); BRCA2 (Breast cancer type 2 susceptibility protein, 13q12.3); BRIP1 (Fanconianemia group J protein, 17q22); FANCL (E3 ubiquitin-protein ligase FANCL).
Inheritance: AR, AD (RAD51)
Clinical Features and Diagnostic Criteria: Short stature; abnlpigmentation; radial, GU, ear, heart, GI, or CNS malformation; hearing loss, hypogonadism, developmental delay. Progressive bone marrow failure, aplastic anemia, myelodysplastic syndrome, AML, solid tumor of head, neck, esophagus, cervix, vulva, or liver at unusually young age.
Clinical Tests: Chromosome breakage, macrocytic rbcs, immunoblot assay of FANCD2 monoubiquitination, increased % of cells in G2 arrest by cell sorting.
Molecular Tests:Seqand Del/Dup analysis FANCA(66%), Seqanalysis FANCB (0.8%), FANCC(9.6%), FANCD1, FANCD2, FANCE, FANCF (~3% each), FANCG (8.8%), FANCL(0.4%) and BRCA2
Disease Mechanism: At least 5 of the FA proteins are assembled in a nuclear complex. In response to DNA damage, this complex activates monoubiquitinationof FANCD2 protein and is targeted to BRCA1 repair foci.
Treatment/Prognosis: Androgens, blood transfusions, growth hormone, BMT, cancer prevention (avoid toxic agents and sun exposure), cancer surveillance