Loeys-Dietz Syndrome 1C: SMAD3

Loeys-Deitz Syndrome, Type 1C
	Gene:	SMAD3; chr15q22.33

Syndrome Information
	Clinical Description:	The clinical features of LDS 1C include aortic aneyrusm and dissection, tortuosity of the arterial tree, mild craniofacial features (hypertelorism, abnormal palate or uvula, dental anomalies), skeletal anomalies (pes planus), cutaneous anomalies (velvety skin, striae, varicies) and early onset osteoarthritis, which is often a presenting symptom. Other cardiovascular anomalies include persistent ductus arteriosis, atrial septal defect, pulmonary valve stenosis, atrial fibrillation, and mitral valve anomalies. Umbilical or inguinal hernia was also reported. No Craniosynostosis, eye abnormalities, or mental retardation were reported. SMAD3 mutations have also been identified in patients with familial Thoracic Aortic Aneurysms and Dissections (TAAD).
	Inheritance Pattern:	Autosomal Dominant
	Genotype-Phenotype Correlation:	Variable expressivity with inter- and intra-familial variability

Test Information
	Test Method:	Bidirectional sequencing of the coding regions and intron-exon boundaries of SMAD3
	Clinical Utility:	Identification of causative mutations in known or highly suspicious cases of Loeys-Dietz Syndrome Type 1C; rule-out of inherited causes of aortic aneurysm; presymptomatic testing for relatives of proband and predictive prenatal testing when familial mutations are known.
	Clinical Sensitivity:	Mutations in SMAD3 were identified in 2% (2/99) of patients with aneurysm and Marfan-like features who tested negative for FBN, TGFBR1, and TGFBR2 mutations and approximately 1% (2/178) of patients with familial or sporadic aneurysm with or without dysmorphic features (van de Laar et al. 2010; Nat Genet 43:121-126). Approximately 2% (4/181) patients with familial thoracic aortic aneurysms and dissections (TAAD) had SMAD3 mutations (Regalado et al. 2011 Circ Res June 21; e-pub ahead of print).
	Analytic Sensitivity:	Greater than 97% for nucleotides analyzed. All reports will indicate if a certain percentage of nucleotides were not called or were analyzed in a single direction.
	Turn Around Time:	4 weeks
	Fee and CPT Codes:	$994 for routine testing on a blood or DNA sample 83898 x 9; 83904 x 18; 83909 x 18; 83912 x 1 Please contact the lab to arrange testing for known mutations on blood or prenatal samples.

Special Considerations
	Like other forms of LDS, LDS 1C is an aggressive aneurysm syndrome that requires diagnosis and treatment at an early stage of disease. This clinical entity was originally reported as Aneurysm Osteoarthritis Syndrome (AOS), with early onset osteoarthritis being the phenotype the authors used to differentiate it from Loeys-Dietz Syndrome. It has since been reclassified as Loeys-Deitz Syndrome Type 1C by OMIM.

	INFORMED CONSENT from the patient is required prior to ordering a genetic test. The DNA Diagnostic Lab's consent is located on the second page of the requisition form. There is also a patient brochure, "Things Every Patient Should Know Before Consenting to a Genetic Test", available for download.
Helpful Links
	Sample Requirements Requisition and Billing forms Clinical information on Loeys-Dietz Syndrome Type 1C Patient and Family Page for general resources on genetic testing.