Small deletions or duplications in the genome are collectively referred to as copy number variants (CNVs). Some CNVs are so common (occurring in >1% of population), that they are referred to as copy number polymorphisms.(1)
Contiguous gene syndromes is a group of disorders caused by deletion that spans several genes, located near each other. Deletions on some chromosomes are more common and produce recognized phenotypes:
- Williams syndrome (chromosome 7q genes deletion)
- Angelman syndrome and Prader-Willi syndrome (15q11-13 deletion)
- DiGeorge syndrome, a.k.a. Velocardiofacial syndrome (22q11.2 deletion)
- WAGR syndrome (11p13 deletion)
Many of these syndromes can be diagnosed by careful history and physical exam. Karyotyping is usually not sufficient to diagnose small deletions, and fluorescent in-situ hybridization (FISH) is needed for genetic diagnosis.
Williams syndrome is a neurodevelopmental disorder characterized by "elfin" facial dysmorphisms, variable MR, and cognitive deficits. Cognitive problems include, most prominently, visual-spatial deficits, affecting handwriting, drawing, gait, and ability to assemble jigsaw puzzles. (This is often contrasted with fragile X syndrome, where cognitive deficits are uniform, and Down syndrome, where visual-spatial abilities may be spared). Notably, many patients with Williams syndrome demonstrate superior musical abilities.
Associated dysmorphic features include short upturned nose, flat nasal bridge, long philtrum, wide mouth and full lips.
Behaviorally, children are often inattentive, hyperactive, overly friendly and hyperverbal (blurting). At the same time many exhibit social and communicative difficulties seen in autism spectrum disorders.
Elastin protein insufficiency accounts for significant cardiovascular disease and arterial stenosis. Hypercalcemia is another clinical feature of the syndrome.
Each autosomal gene is represented by two copies (alleles), one from each parent; in some instances only one copy is expressed, while the other is silenced. This phenomenon is referred to as genetic imprinting. Chromosomal region 15q11-13 contains genes whose expression depends on whether the chromosome is maternal or paternal in origin. For example UBE3A gene is only expressed by the maternal chromosome, and invariably silenced on the paternal copy. A loss of 15q11-13 segment of the maternal chromosome will result in Angelman syndrome, since the normal paternal copy contains a silenced copy of UBE3A.
- If the deletion is relatively small, genetic diagnosis requires analysis of methylation patterns using Southern Blot of PCR.
- Paternal chromosome 15 uniparental disomy is a rare cause of Angelman syndrome.
Individuals with Angelman syndrome are hypotonic as infants, and develop with significant motor delays and MR. Speech and expressive language are delayed or absent. A characteristic gait ataxia and a happy, easily excitable demeanor were captured in the older term happy puppet syndrome. Early seizures and microcephaly are common features.
- Associated dysmorphic features include large mandible, wide mouth, and wide-spaced teeth.
- Prevalence is about 1 in 10,000 births.
Prader-Willi syndrome (PWS) results from 15q11-13 deletion on the paternal chromosome. The corresponding genes on the maternal chromosome are silenced and thus, not expressed. Infants are lethargic and hypotonic at birth; they often have feeding difficulties resulting in failure to thrive. Speech and other developmental delays follow.
- Hyperphagia becomes significant by second or third year of life, contributing to obesity.
- Children with PWS have mild to moderate ID, behavioral difficulties and temper tantrums, obsessive-compulsive and skin picking behaviors.
- Dysmorphic features include narrow forehead, elongated face, downward-slanted palpebral fissures, small hands and feet.
- Scoliosis and hypogonadism are features that often go unrecognized.
Prevalence is about 1 in 10,000 births.
Also known as DiGeorge syndrome, it involves deletion or mutation of TBX1 gene on 22q11 chromosome.
The syndrome is associated with increased risk of schizophrenia and bipolar disorders in 10-30% of patients.
(1) Morrow EM. Genomic Copy Number Variation in Disorders of Cognitive Development. JAACAP, 2010;49(11):1091-1104.