The Principles of Clinical Cytogenetics - Extra Materials - Springer

Fluorescence In Situ Hybridization 459
Table 1
Microdeletion Syndromes
Syndrome Deletion Probe a Phenotype
Angelman 15q11.2–15q13 SNRPN, Severe mental retardation; hypotonia; ataxia; lack of
D15S10 speech; hypopigmentation; seizures; inappropriate
laughter; dysmorphic features
DiGeorge 22q11.2 D22S75 Dysmorphic features, congenital heart disease; absence
of thymus; growth failure; cognitive deficits
Miller–Dieker 17p13.3 LIS1 Severe mental retardation; lissencephaly; dysmorphic
facial features
Prader–Willi 15q11.2–15q13 SNRPN Mental retardation; hypotonia; feeding difficulty; genital
hyperplasia; obesity; hyperphagia; dysmorphic features
Smith Magenis 17p11.2 SHMT1, Mental retardation; speech delay; bizarre behavior;
TOP3, peripheral neuropathy; dysmorphic facial features
FLI1,
LLGL1
Velocardiofacial 22q11.2 TUPLE1 Delayed development; pharyngeal deficiency; abnormal
facies; palatal defects; congenital heart defects
Williams 7q11.2 ELN Mental retardation, hypercalcemia; elfin facies;
gregarious personality; congenital heart disease
a The FISH probes used to diagnose the syndrome are listed in this column and are all commercially available.
drome resulting from a duplication of this region [dup(17)(p11.2p11.2)] (11), both of which can be
diagnosed using FISH with probes from the critical region. Interphase FISH with a probe for a 1.4 Mb
area of 17p12 is used to detect the duplication associated with Charcot–Marie–Tooth disease 1A. This
same region is deleted in patients with hereditary neuropathy with liability to pressure palsies (HNPP).
Microdeletions of 22q11.2, resulting in velocardiofacial (VCF) or DiGeorge syndrome, are seen
in about 1/2000 to 1/3000 individuals. Because of the frequency of this syndrome and its association
with congenital heart disease, fetuses and newborns with a heart defect are routinely studied for a 22q
deletion. This syndrome, in contrast to other microdeletion syndromes, is inherited in about 10% of
the cases. Therefore, FISH studies of parents of an affected individual are recommended. The deletions
involve approximately 2 Mb of DNA and are easily detected by FISH with the TUPLE1 probe
or a probe for the DNA segment D22S75. The majority of these deletions, which are also mediated by
repetitive duplicated regions, occur at the same proximal and distal breakpoint (12). Duplications of
22q11.2 are associated with dysmorphic features, growth failure, cognitive deficits, hearing loss, and
velopharyngeal insufficiency (13).
Williams syndrome involves the loss of the genes in the long arm of chromosome 7 at band q11.23.
The deletion has two major breakpoints that are mediated by LCRs. The deletion cannot be detected
by G-banding, but it can routinely be detected by FISH with a probe for the elastin (ELN) gene.
Phenotypic features seen in this syndrome elegantly demonstrate the definition of a contiguous gene
syndrome, as Williams syndrome involves both the central nervous system and connective tissue
abnormalities. Abnormalities include mental retardation, infantile hypercalcemia, elfin facies,
dsymorphic facial features, a gregarious personality, premature aging of the skin, and a congenital
heart disease (supravalvular aortic stenosis) (14).
Cryptic Subtelomeric Rearrangements
It is generally accepted that even with high-resolution chromosome analysis, alterations of chromosomal
material of less than 2–4 Mb cannot be detected. Translocations or insertions involving
segments below this threshold may be visualized with M-FISH (see below). In particular, recognition