22q and two: 22q11.2 deletion syndrome and coexisting conditions

Abstract

22q11.2 deletion syndrome (DS) is the most frequent copy number variant (CNV) affecting ~1/1,000 fetuses and ~1/2,000–4,000 children, resulting in recognizable but variable findings across multiple organ systems. Patients with atypical features should prompt consideration of coexisting diagnoses due to additional genome-wide mutations, CNVs, or mutations/CNVs on the other allele, unmasking autosomal recessive conditions. Importantly, a dual diagnosis compounds symptoms and impacts management. We previously reported seven patients with 22q11.2DS and: SCID, Trisomy 8 mosaicism, Bernard-Soulier, and CEDNIK syndromes. Here we present six additional unreported patients with 22q11.2DS and concurrent diagnoses. Records on 1,422 patients with 22q11.2DS, identified via FISH, microarray, or MLPA, followed in our 22q and You Center at the Children’s Hospital of Philadelphia (CHOP) were reviewed to identify a dual diagnosis. In addition to our seven previously reported cases, we identified an additional six with 22q11.2DS and another coexisting condition identified via: molecular/cytogenetic studies, newborn screening, coagulation factor studies, or enzyme testing; these include CHARGE syndrome (CHD7 mutation), cystic fibrosis, a maternally inherited 17q12 deletion, G6PD deficiency, von Willebrand disease, and 1q21.1 deletion, resulting in an incidence of dual diagnoses at our center of 0.9%. The range of dual diagnoses identified in our cohort is notable, medically actionable, and may alter long-term outcome and recurrence risk counseling. Thus, our findings may support testing patients with 22q11.2DS using a combination of microarray, mutational analysis of the other allele/WES, to ensure appropriate personalized care, as formulating medical management decisions hinges on establishing the correct diagnoses in their entirety.

Social, neurodevelopmental, endocrine, and head size differences associated with atypical deletions in Williams–Beuren syndrome

“…Rather, the existence of a second diagnosis should be considered and additional molecular diagnostics sought, either through the use of CMA, focused gene panel testing, or exome. Studies in 22q11.2 deletion syndrome, for example, have shown a second diagnosis rate of nearly 1% in their patients (Cohen et al, ).…”

The Genetics and Epigenetics of 22q11.2 Deletion Syndrome

“…In an analysis of >1400 22q11.2del patients, 1% were found to have secondary mutations at other loci (Michaud et al, 1995;Mcdonald-Mcginn et al, 2013;Kruszka et al, 2017). These secondary mutations, including some affecting the presumed normal allele of chromosome 22q11.2, are resulting in dual diagnoses (Cohen et al, 2018). A few of the more prominent diagnoses include CHARGE (Coloboma, heart defects, atresia choanae, growth retardation, genital and ear anomalies) syndrome, cystic fibrosis, G6PD deficiency, 17q12 deletion syndrome, and von Willebrand disease (Michaud et al, 1995;Mcdonald-Mcginn et al, 2013;Cohen et al, 2018).…”

“…These secondary mutations, including some affecting the presumed normal allele of chromosome 22q11.2, are resulting in dual diagnoses (Cohen et al, 2018). A few of the more prominent diagnoses include CHARGE (Coloboma, heart defects, atresia choanae, growth retardation, genital and ear anomalies) syndrome, cystic fibrosis, G6PD deficiency, 17q12 deletion syndrome, and von Willebrand disease (Michaud et al, 1995;Mcdonald-Mcginn et al, 2013;Cohen et al, 2018). Whether these secondary mutations at distinct loci influence the expression of genes on chromosome 22q11.2 has not been assessed.…”

Espectro fenotípico de Síndrome de CHARGE neonatal

“…Otros diagnósticos diferenciales del síndrome de CHARGE son el síndrome de Kabuki, síndrome renalcoloboma, síndrome de Cat-Eye, síndrome de Joubert, síndrome Branquio-Oto-Renal, embriopatía secundaria a exposición a ácido retinoico y asociación VAC-TERL 10,11,17,18 .…”

“…Considerando la prevalencia descrita, (en Chile debiéramos tener 20 casos al año), creemos que hay una alta tasa de subdiagnóstico debido a la sobreposición de síntomas con otros síndromes y la alta morbimortalidad en periodo neonatal. Entre los diagnósticos diferenciales está el síndrome de microdeleción 22q11.2, síndrome de Kallman, síndrome de Kabuki, Treacher Collins, Mowat Wilson y síndrome 3M 10,11 .…”