Microdeletion syndromes are conditions characterized by small deletions of DNA, generally 5 Mb or less, that cause a specific collection of clinical features (Carvill and Mefford, 2013; Datar, 2014). The loss of DNA typically results in haploinsufficiency for critical genes in a given chromosomal region (Datar, 2014). Historically, microdeletion syndromes were detected via standard high resolution karyotype analysis; but with the onset of more sophisticated molecular cytogenetic techniques such as fluorescence in situ hybridization (FISH) and chromosomal microarray (CMA), many more disorders have been able to be attributed to microdeletions (Carvill and Mefford, 2013).

Some well-known microdeletion syndromes include: 22q11.2 deletion syndrome (aka Velocardiofacial syndrome; DiGeorge syndrome), Smith-Magenis syndrome, and Williams syndrome. 

22q11.2 Deletion syndrome

22q11.2 deletion syndrome is an autosomal dominant contiguous gene deletion syndrome. Other names for this condition include velocardiofacial syndrome (VCFS) and DiGeorge syndrome. There is significant phenotypic heterogeneity among individuals with this condition. Affected individuals have multiple symptoms, including characteristic facial features, palate abnormalities, congenital heart defects, learning disabilities, hypocalcemia, and immune deficiency(McDonald-McGinn et al., 1999). Many other features have also been associated in lesser frequency including psychiatric disease, hearing loss, and growth hormone deficiency (McDonald-McGinn et al., 1999; Verheij et al., 2017; Campbell et al., 2018). In the prenatal period, this condition may be suspected based on ultrasound detection of a congenital heart defect and/or a cleft lip/palate (Schindewolf et al., 2018).

More than 90% of individuals have a de novo deletion, with about 10% of cases being inherited from an affected parent (McDonald-McGinn et al., 1999). A minority of cases may be due to specific point pathogenic/likely pathogenic (P/LP) variants in the TBX1 gene located within this region, which is primarily associated with congenital cardiac anomalies (Hacihamdioglu et al., 2015; Hasegawa et al., 2018). It has been suggested that other inherited factors may modify the phenotype of an individual with 22q11.2 deletion syndrome, but currently there is insufficient data to support clinical testing of additional genes to predict prognosis (Morrow et al., 2018).

Clinical practice guidelines for the care and management of individuals with 22q11.2 deletion syndrome have been published. These focus on neuropsychiatric, endocrine, cardiovascular, reproductive, psychosocial, genetic counseling, and other issues that present in all stages of life (Bassett et al., 2011; Fung et al., 2015). Given the variable expressivity associated with this condition, parents and siblings of affected individuals may benefit from clinical evaluations or genetic testing as well (Campbell et al., 2018).

Smith-Magenis Syndrome

Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder associated with intellectual delays, speech delays, behavioral disturbances, and sleep disturbances. Characteristic features of SMS include ophthalmologic abnormalities, short stature, a distinctive facial appearance, minor skeletal anomalies, failure to thrive, mild-to-moderate infantile hypotonia, brachydactyly, otolaryngologic abnormalities, speech delays, peripheral neuropathy, cognitive impairment/developmental delay, and other stereotypic behaviors (Smith et al., 2001). Increased sensitivity to sound (hyperacusis) has been observed in more than 70% of individuals with SMS (Brendal et al., 2017).

The diagnosis of SMS can be confirmed with the identification of an abnormality involving the RAI1 gene. Chromosomal microdeletions at 17p11.2 or RAI1 deletions account for 95% of causal variants. RAI1 sequence variants account for approximately 5-10% of SMS cases (Dubourg et al., 2014). 

Williams Syndrome

Williams syndrome is associated with a contiguous gene deletion on chromosome 7 that encompasses a critical region including the ELN gene (Morris, 1999). Williams syndrome is characterized by heart defects (often supravalvar aortic stenosis), distinctive facial features, connective tissue abnormalities, intellectual disability, unique personality characteristics, growth abnormalities, and endocrine abnormalities (Morris, 1999; Brink et al., 2022). The diagnosis of Williams syndrome can be made by identification of the 1.5-1.8-Mb microdeletion at chromosome 7q11.23, either by CMA or FISH (Morris, 1999).