What statistical term best describes the relationship between 22q11.2 (22q11.2 deletion syndrome) deletion syndrome and conotruncal congenital heart disease?

Association is the Statistical Term that Best Describes the Relationship Between 22q11.2 Deletion Syndrome and Conotruncal Congenital Heart Disease

Association is the statistical term that best describes the relationship between 22q11.2 deletion syndrome and conotruncal congenital heart disease, as there is a significant but not universal co-occurrence of these conditions.

Evidence for Association

• 22q11.2 deletion syndrome (22q11.2DS) is strongly associated with conotruncal cardiac defects, with approximately 60-70% of individuals with the typical 3 megabase deletion from LCR22A-D having congenital heart disease, mostly of the conotruncal type 1
• This relationship represents an association rather than a normal distribution, bell curve, or bimodal distribution because:
  • The presence of one condition significantly increases the likelihood of the other, but does not guarantee it 1, 2
  • The relationship is not characterized by a symmetrical distribution around a mean (which would be a normal distribution or bell curve) 2
  • The data does not show two distinct peaks of frequency that would characterize a bimodal distribution 1, 2

Cardiac Manifestations in 22q11.2DS

• Congenital heart defects are among the primary features that lead to suspicion of 22q11.2DS in patients 3
• Tetralogy of Fallot is the most frequent heart defect in children with 22q11.2DS and conotruncal defects 2, 4
• Other common cardiac anomalies include:
  • Ventricular septal defect 4
  • Atrial septal defect 4
  • Aortic arch anomalies, which significantly increase the likelihood of 22q11.2DS regardless of the intracardiac anatomy 2

Genetic Basis of the Association

• The TBX1 gene within the 22q11.2 region is highlighted as the most widely studied gene associated with conotruncal cardiac anomalies in both animal models and humans 3
• CRKL (CRK-like proto-oncogene) has been implicated as a modifier gene affecting the penetrance of cardiac defects in 22q11.2DS 1
• Common variants in a 350 kb interval harboring CRKL show significant association with risk for conotruncal defects in 22q11.2DS patients 1

Clinical Implications of this Association

• Screening for 22q11.2 microdeletion should be performed in children with conotruncal heart defects who have at least one additional feature of 22q11.2DS 4
• Mortality rates in children with 22q11.2DS range from 5% to 15%, with most deaths occurring during the first year of life, primarily related to complex congenital heart disease 3
• The death rate in children with 22q11.2DS and congenital heart defects is greater than that of children with comparable heart defects without 22q11.2DS 3
• Patients with 22q11.2DS planning pregnancy should receive genetic counseling, as their offspring have an increased risk of congenital heart defects 3

Variability in the Association

• Not all patients with 22q11.2DS have cardiac defects, and not all patients with conotruncal defects have 22q11.2DS, confirming this is an association rather than a deterministic relationship 1, 2
• In studies of non-syndromic patients with isolated cardiac defects, no association with 22q11.2 microdeletion was observed 5
• Additional genetic modifiers outside the 22q11.2 region may influence the risk of congenital heart defects in this population, such as duplications of SLC2A3 6