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Pediatrics - Cardiology

Houston, Texas

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Pediatrics - Cardiology
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SMAD4 Mutation Analysis

SMAD4 gene encodes a member of the SMAD family of signal transduction proteins that are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to TGF-beta signaling. SMAD4 forms homomeric complexes and heteromeric complexes with other activated SMAD proteins, which then accumulate in the nucleus and regulate the transcription of target genes. It binds to DNA and recognizes an 8-bp palindromic sequence (GTCTAGAC) called the SMAD-binding element (SBE). SMAD4 gene contains 11 exons spanning 55 kb of genomic distance that was mapped to chromosome 18q21.1. Multiple mutations in SMAD4 have been identified in patients with juvenile polyposis/heriditary hemorrhagic telangiectasia syndrome, aortopathy, primary pulmonary hypertension, Myhre syndrome, Peutz-Jeghers syndrome, prostate cancer, pancreatic cancer and coloractal cancer. SMAD4 mutations demonstrate autosomal dominant inheritance with a broad range of clinical severity both within and between families. Definitive genotype/phenotype correlations have not been described.

The John Welsh Cardiovascular Diagnostic Laboratory offers molecular genetic testing for SMAD4 mutations. Individuals are tested by automatic fluorescent DNA sequencing of the coding exons of the SMAD4 gene. We strongly recommend initial testing of a clearly affected individual, if available, in order to provide the greatest test sensitivity and clearest interpretation of results for subsequent family members. Genetic counseling is recommended for all individuals.

Reasons for Referral

Molecular confirmation of juvenile polyposis/heriditary hemorrhagic telangiectasia syndrome, aortopathy, primary pulmonary hypertension, Myhre syndrome, Peutz-Jeghers syndrome, prostate cancer, pancreatic cancer and coloractal cancer.

Methodology

Genomic DNA is analyzed for SMAD4 mutations by automatic fluorescent DNA sequencing of the coding exons of the SMAD4 gene, as well as the exon/intron junctions and a portion of the 5' and 3' untranslated region. Patient DNA is sequenced in both the forward and reverse orientations. If a mutation is identified, additional family members are analyzed only for the familial mutation by automatic fluorescent DNA sequencing.

Service Fees

Service Direct and Institutional Billing CPT Codes
Index Case (Male or Female) $750 per sample 81406, G0452
Additional Family Members $300 per sample; known familial mutation only 81403, G0452

Sensitivity

DNA Sequencing Analysis: Approximately 99 percent detection of mutations in exons 1-11 of SMAD4

Specimen Requirements

Blood (preferred): EDTA (purple-top) tubes: Adult: 5 cc, Child: 5 cc, Infant: 2-3 cc
Tissue: Frozen (preferred), RNAlater, Formalin-fixed, Paraffin-embedded
Other Body Fluids: Call to inquire
Buccal Swabs: One swab from each cheek

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