Microdeletion Gene Syndromes

By Nina N. Powell-Hamilton, MD, FAAP, FACMG, Alfred I. duPont Hospital for Children ;Thomas Jefferson University Medical College

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Microdeletion syndromes are disorders caused by microscopic and submicroscopic deletions or duplications of contiguous genes on particular parts of chromosomes. Postnatal diagnosis is suspected by clinical appearance and confirmed by fluorescent in situ hybridization and chromosomal microarray analysis.

Microdeletion syndromes differ from chromosomal deletion syndromes in that deletion syndromes are usually visible on karyotyping because of their larger size (typically > 5 megabases), whereas the abnormalities in microdeletion syndromes involve smaller segments (typically 1 to 3 megabases) and are detectable only with fluorescent probes (fluorescent in situ hybridization) and microarray analysis. A given gene segment can be deleted or duplicated (termed a reciprocal duplication). The clinical effects of microscopic reciprocal duplications tend to be similar but less severe than those of deletions involving the same segment. The term contiguous gene syndrome encompasses both microdeletion syndromes and contiguous abnormalities visible on karyotyping.

Most clinically significant microdeletions and duplications seem to occur sporadically; however, mildly affected parents may be diagnosed when parental testing is done after a child is found to have an abnormality. Numerous syndromes have been identified, with widely varying manifestations (see Table: Examples of Microdeletion Syndromes).

Examples of Microdeletion Syndromes

Syndrome	Chromosomal Deletion	Description
Alagille syndrome	20p.12	Cholestasis, bile duct paucity, cardiac anomalies, pulmonary artery stenosis, butterfly vertebrae, posterior embryotoxon of the eye
Angelman syndrome	Maternal chromosome at 15q11	Seizures, puppet-like ataxia, frequent laughter, hand flapping, severe intellectual disability
DiGeorge syndrome (DiGeorge anomaly, velocardiofacial syndrome, pharyngeal pouch syndrome, thymic aplasia)	22q11.21	Hypoplasia or lack of thymus and parathyroids, cardiac anomalies, cleft palate, intellectual disability, psychiatric problems
Langer-Giedion syndrome (trichorhinophalangeal syndrome type II)	8q24.1	Exostosis, cone epiphyses, sparse hair, bulbous nose, hearing loss, intellectual disability
Miller-Dieker syndrome	17p13.3	Lissencephaly; short, upturned nose; severe growth retardation; seizures; severe intellectual disability
Prader-Willi syndrome	Paternal chromosome at 15q11	In infancy: Hypotonia, poor feeding, failure to thrive In childhood and adolescence: Obesity, hypogonadism, small hands and feet, intellectual disability, obsessive-compulsive behaviors
Rubinstein-Taybi syndrome	16p13−	Broad thumbs and large toes, prominent nose and columella, intellectual disability
Smith-Magenis syndrome	17p11.2	Brachycephaly, midfacial hypoplasia, prognathism, hoarse voice, short stature, intellectual disability
Williams syndrome	7q11.23	Aortic stenosis, intellectual disability, elfin facies, transient hypercalcemia in infants