Congenital Heart Defects and 22q11.2 Deletion Syndrome: A 20-Year Update and New Insights to Aid Clinical Diagnosis

Abstract

Congenital heart defects (CHDs) are one of the most prevalent clinical features described in individuals diagnosed with 22q11.2 deletion syndrome (22q11.2DS). Therefore, cardiac malformations may be the main finding to refer for syndrome investigation, especially in individuals with a mild phenotype. Nowadays, different cytogenetic methodologies have emerged and are used routinely in research laboratories. Hence, choosing an efficient technology and providing an accurate interpretation of clinical findings is crucial for 22q11.2DS patient's diagnosis.This systematic review provides an update of the last 20 years of research on 22q11.2DS patients with CHD and the investigation process behind each diagnosis. A search was performed in PubMed, Embase, and LILACS using all entry terms to DiGeorge syndrome, CHDs, and cytogenetic analysis. After screening, 60 papers were eligible for review. We present a new insight of ventricular septal defect as a possible pivotal cardiac finding in individuals with 22q11.2DS. Also, we describe molecular technologies and cardiac evaluation as valuable tools in order to guide researchers in future investigations.

In-Depth Genomic Analysis: The New Challenge in Congenital Heart Disease

“…Cytogenetic analyses and genomic arrays have aided in the understanding of subchromosomal structural rearrangements. These analyses have highlighted frequent 3 Mb deletions, which are also associated with DiGeorge (velocardiofacial) syndrome [10][11][12][13]. Deletions of 22q11.2, as determined by fluorescence in situ hybridisation (FISH) [14,15] and targeted amplification [16], are present in approximately 2% of all cases of congenital heart disease and in 13% of individuals with selected heart malformations.…”

“…Most human variants have a heterozygous dosage, and while experimental models usually examine homozygous variants, data on congenital heart disease obtained from human studies can reveal information about less obvious impacts on heart formation. Furthermore, patients with critical and complex malformations display the greatest frequency of de novo damaging variants in genes linked to CHD, which provides convincing evidence of severe adverse effects on reproductive health and the evolutionary restriction on numerous genes connected with CHD [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. Figure 3.…”

Primary and secondary defects of the thymus

“…The clinical manifestation with the most significant comorbidity in 22q11.2del is CHD (ventriculo‐septal defect, Tetralogy of Fallot, truncus arteriosus). It is present in half of the DGS patients, and it is the leading cause of death 140,141 . Hypoparathyroidism is also present in 50% of patients; it results in clinically significant hypocalcemia manifesting as neonatal seizures, feeding difficulties, and weight loss 142 .…”

“…It is present in half of the DGS patients, and it is the leading cause of death. 140,141 Hypoparathyroidism is also present in 50% of patients; it results in clinically significant hypocalcemia manifesting as neonatal seizures, feeding difficulties, and weight loss. 142 Monitoring of calcium levels and prompt calcium supplementation are especially important in situation of stress, such as infections, pregnancy, and puberty.…”

In-Depth Genomic Analysis: The New Challenge in Congenital Heart Disease

“…[9] Cytogenetic analysis and genomic arrays have helped to understand subchromosomal structural rearrangements, highlighting frequent 3-Mb deletions at 22q11.2 in DiGeorge (velocardiofacial) syndrome. [10][11][12][13] Deletions are present in approximately 2% of all cases of CHD and in 13% of individuals with specific cardiac malformations, as determined by fluorescence in situ hybridization [14,15] and targeted amplification. [16] About 25% of sporadic CHD cases are caused by the coexistence of karyotype or microarray-detected abnormalities.…”