The Principles of Clinical Cytogenetics - Extra Materials - Springer

354 Xiao-Xiang Zhang
patients, greatly limits the utility of direct mutation analysis as a diagnostic tool, except where founder
effect mutations are involved.
Nijmegen Breakage Syndrome
Nijmegen breakage syndrome (NBS) is a rare disorder characterized by microcephaly, a “birdlike”
face, growth retardation, lack of secondary sex development in females, immunodeficiency,
and cancer predisposition. Because cells from NBS patients share cytogenetic features with A-T,
such as spontaneous chromosome instability, clonal rearrangements (preferentially involving chromosomes
7 and 14), and hypersensitivity to ionizing radiation, NBS was originally thought to be a
variant of A-T (35). Clinical features differ; however. NBS patients have microcephaly but neither
cerebellar ataxia nor telangiectasias and have normal serum levels of AFP. Complementation studies
and, moreover, the recent identification of the genes responsible for A-T (ATM) and for NBS (NBS1;
Nibrin, or p95 protein of the NBS1/Mre11/Rad50 complex) (36,37) have proven that A-T and NBS
are related but separate entities.
Several lines of evidence have suggested that ATM and NBS1 functionally interact in response to
DNA damage induced by ionizing radiation (IR). Zhao et al. showed that NBS1 is phosphorylated by
ATM in response to DNA damage. This involves S-phase checkpoint activation, formation of NBS1/
Mre11/Rad50 nuclear foci, and reversal of IR damage (38). This observation links ATM and NBS1
in a common signaling pathway and provides an explanation for the phenotypic similarities between
these two disorders.
A 5-bp truncating deletion (657Del5) has been identified in 90% of NBS patients. Recently a German
group found a high carrier frequency (1/177) of 657Del5 mutations in three Slavic populations (39,40).
ICF Syndrome
ICF (Immunodeficiency, Centromere instability, and Facial anomalies) syndrome is a recessive
disorder resulting from mutations in the DNA methyltransferase 3B (DNMT3B) gene (41). ICF syndrome
is the only genetic disorder known to involve constitutive abnormalities of genomic methylation
patterns.
ICF patients present with variable reductions in serum immunoglobulin levels. Mild facial
dysmorphic features include hypertelorism, low-set ears, epicanthal folds, and macroglosia. Cytogenetic
analysis of peripheral blood lymphocytes reveals multiradial configurations and a stretching of
the pericentromeric heterochromatin of chromosomes 1, 9, and 16 (see Fig. 4). An increase in formation
of micronuclei is also noted in ICF patients. Using FISH studies probes specific for alphoid
satellite DNA (centromere), and classical satellite II DNA (paracentric heterochromatin), Sumner et
al. (42) showed that it is always the paracentromeric heterochromatin of chromosomes 1, 9, and 16
that becomes decondensed and fused to form multriradial configurations. The centromeric regions
remain outside the regions of interchange. These same juxtacentromeric heterochromatin regions are
subjected to persistent interphase self-associations and are extruded into nuclear blebs or micronuclei.
Studies of the molecular phenotype of ICF cells revealed that extensive hypomethylation is
associated with advanced replication time, nuclease hypersensitivity, and variable escape from silencing
for genes on the Y and inactive X chromosomes (43).
Robert Syndrome
Robert syndrome (RS) is characterized by craniofacial anomalies, limb defects, and prenatal and
postnatal growth retardation. RS patients present with various degrees of limb malformations, involving
symmetric phocomelia or hypomelia. Hypertelorism and cleft lip and palate are often seen in
affected individuals. Despite the heterogeneous clinical presentation, complementation studies of
cells derived from RS patients defined a single complementation group in RS (44). Premature centromere
separation, centromere splitting, and puffing of heterochromatic regions near centromeres,