Coexisting Conditions Modifying Phenotypes of Patients with 22q11.2 Deletion Syndrome

Abstract

22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder with an extremely broad phenotypic spectrum. The aim of our study was to investigate how often the additional variants in the genome can affect clinical variation among patients with the recurrent deletion. To examine the presence of additional variants affecting the phenotype, we performed microarray in 82 prenatal and 77 postnatal cases and performed exome sequencing in 86 postnatal patients with 22q11.2DS. Within those 159 patients where array was performed, 5 pathogenic and 5 likely pathogenic CNVs were identified outside of the 22q11.2 region. This indicates that in 6.3% cases, additional CNVs most likely contribute to the clinical presentation. Additionally, exome sequencing in 86 patients revealed 3 pathogenic (3.49%) and 5 likely pathogenic (5.81%) SNVs and small CNV. These results show that the extension of diagnostics with genome-wide methods can reveal other clinically relevant changes in patients with 22q11 deletion syndrome.

Neuropsychological Profile of 25 Brazilian Patients with 22q11.2 Deletion Syndrome: Effects of Clinical and Socioeconomic Variables

“…The estimated minimum prevalence of 22q11.2 deletions was 1 in 2148 (4.7 per 10,000) live births [1]. Most patients have approximately a ≈3 megabase (Mb) deletion, with less frequent occurrences of deletions of 2 Mb or about 1.5 Mb [1][2][3].…”

“…The main clinical conditions observed in 22q11.2DS deletion syndrome include congenital heart diseases, immunodeficiency from thymic hypoplasia/aplasia, velopharyngeal dysfunction (with or without cleft palate), and hypocalcemia resulting from hypoparathyroidism [1][2][3][4][5][6]. Patients with 22q11.2DS have a high risk of developing epilepsy [7], reported in 11% of cases [8].…”

Variants in KMT2A in Three Individuals with Previous Suspicion of 22q11.2 Deletion Syndrome

“…The condition known as 22q11.2 deletion syndrome (22q11.2DS) (MIM #188400) is a rare disease with autosomal dominant inheritance caused by heterozygous deletions of the 22q11.2 locus, usually occurring as de novo mutations. Its prevalence has been estimated to range from 1:3000 to 1:6000 live births, based on the diagnosis of infants with major birth defects and a few population screening studies conducted between the early 1990s and early 2000s using FISH technology, and it is considered the most frequent microdeletion in humans [1][2][3][4][5].…”

“…The most common features of 22q11.2DS include congenital heart disease, developmental delay, intellectual disability, palatal defects, immunodeficiency, endocrine abnormalities, and behavioral and psychiatric disorders. Nevertheless, the clinical picture is highly variable in presentation and severity and might include less frequent features in a list of more than 180 manifestations [2,3,5]. This remarkable clinical heterogeneity represents a diagnostic challenge, often delaying appropriate treatment and genetic counseling [3], and there is a broad range of differential diagnoses, including chromosomal abnormalities, monogenic conditions, polygenic disorders, and non-genetic causes.…”

“…Next-generation sequencing technologies such as whole-exome sequencing (WES) or whole-genome sequencing (WGS) have facilitated the reverse phenotyping approach in opposition to the phenotype-first approach [9]; that is, when the detection of a causative genetic abnormality conducts to a previously unobserved clinical phenotype indicating the diagnosis. Due to its high populational frequency, 22q11.2DS might also cooccur with other conditions, resulting in dual diagnosis [3,5]. Thus, the most recent tendency in clinical practice is to utilize a more broad approach combining different genomic tests for the detection of copy number variants and single-nucleotide variants in the same individual.…”