Neuropsychiatric aspects of 22q11.2 deletion syndrome: considerations in the prenatal setting

Abstract

Most major neuropsychiatric outcomes of concern to families are not detectable by prenatal ultrasound. The introduction of genome-wide chromosomal microarray analysis to prenatal clinical diagnostic testing has increased the detection of pathogenic 22q11.2 deletions, which cause the most common genomic disorder. The recent addition of this and other microdeletions to non-invasive prenatal screening methods using cell-free fetal DNA has further propelled interest in outcomes. Conditions associated with 22q11.2 deletions include intellect ranging from intellectual disability to average, schizophrenia and other treatable psychiatric conditions, epilepsy, and early-onset Parkinson’s disease. However, there is currently no way to predict how severe the lifetime expression will be. Available evidence suggests no major role in these neuropsychiatric outcomes for the congenital cardiac or most other structural anomalies that may be detectable on ultrasound. This article provides an outline of the lifetime neuropsychiatric phenotype of 22q11.2 deletion syndrome that will be useful to clinicians involved in prenatal diagnosis and related genetic counselling. The focus is on information that will be most relevant to two common situations: detection of a 22q11.2 deletion in a fetus or newborn, and new diagnosis of 22q11.2 deletion syndrome in a parent without a previous molecular diagnosis.

Elucidating the diagnostic odyssey of 22q11.2 deletion syndrome

“…We constructed a multivariable linear regression model to examine potential contributors to time to molecular diagnosis of 22q11.2DS (i.e., “diagnostic delay”), defined as the number of years to molecular diagnosis from either 1994 (the year clinical FISH testing was widely available to the samples studied) or year of birth (given the importance of early diagnosis [Bales et al, 2010; Bassett et al, 2017; Cheung et al, 2014; Costain et al, 2012; McDonald-McGinn et al, 2015]), whichever came later. The variables selected, in addition to the birth-cohort subgroups, ethnicity and sex, were three classic developmental features of 22q11.2DS (cardiac anomaly, palatal anomaly, and DD/ID).…”

“…Associated manifestations include classic developmental features such as birth defects and intellectual disability, and later onset features such as schizophrenia [Bassett et al, 2011; Fung et al, 2015; McDonald-McGinn et al, 2015]. Variable expression across the lifespan involves multiple organ systems, with substantial morbidity and mortality, beginning prenatally [Bales et al, 2010; Bassett et al, 2009; Bassett et al, 2005; Bassett et al, 2017; Bassett et al, 2011; Cheung et al, 2014; Costain et al, 2012; Fung et al, 2015; Gerdes et al, 2001; McDonald-McGinn et al, 2015]. Penetrance for one or more of the many associated features is high; typical 22q11.2 deletions are not found in large population control samples [Cooper et al, 2011].…”

Noninvasive screening by cell‐free DNA for 22q11.2 deletion: Benefits, limitations, and challenges

“…However, ultrasound abnormalities in fetuses with 22q11.2DS are quite common. In a population of 272 fetuses with 22q11.2DS, the diagnosis was prompted by abnormal ultrasound findings in 86.8% of the cases . Of note, at least one conotruncal and nonconotruncal cardiac defect was identified in 83.3% of this cohort.…”

“…Common postnatal phenotypic findings include growth and developmental delay, cardiac defects, cleft palate, recognizable facial features, learning disabilities, and immunodeficiency . Regarding prenatal cases, to date, there is no data on the detection rate of 22q11.2DS by second trimester detailed ultrasound in an unselected average risk population.…”

Prenatal testing for neuropsychiatric disorders

“…The neuropsychiatric aspects of 22q11.2 deletion syndrome represent a primary concern of parents who have a fetus at risk or affected by this syndrome. As explained by Bassett et al, 11 gene expression is variable, with intellectual abilities ranging from normal to disabled, and the possible associated manifestations include schizophrenia, seizures, and a motor disorder resembling Parkinson's disease. Genetic counseling for the neuropsychiatric aspects of this syndrome is especially complex given the difficulty at predicting the phenotype, even when one parent is affected.…”