The Principles of Clinical Cytogenetics - Extra Materials - Springer

520 Jin-Chen Wang
3. Imprinting certer mutation in the gene cluster IGF2/H19 or KCNQ1/KCNQ1OT1 (108). In familial cases,
the segregation appears to be autosomal dominant with incomplete penetrance (102). Furthermore, penetrance
appears to be more complete with maternal inheritance; that is, there is an excess of transmitting
females (109,110).
4. Mutation in the maternally active CDKNIC (p57 KIP2 ) gene (111). CDKNIC , a cyclin-dependent kinase
inhibitor, is a negative regulator of cell proliferation; its overexpression arrests cells in G1. Germline
CDKNIC mutations have been found in 40% of familial and 5% of sporadic BWS cases (112).
Linkage studies confirm that BWS maps to 11p15 (113,114). Imprinted genes in this region have
been shown to consist of two domains separated by nonimprinted genes (115,116). The proximal
centromeric domain contains CDKNIC (p57 KIP2 ) (maternal allele active) (117,118), KCNQ1 (maternal
allele active), and KCNQ1OT1 (LIT1) (paternal allele active) (108,119). The distal telomeric
domain contains H19 (maternal allele active) and IGF2 (paternal allele active). The paternally
expressed genes are growth promoter genes, whereas the maternally expressed genes are growth
suppressor genes. Functional imbalance between the growth promoter and growth suppressor genes
causes the phenotype seen in BWS. In some BWS patients who inherited an 11p15 allele from both
parents, an altered pattern of allelic methylation of H19 and IGF2 has been reported (104,120). In
these patients, a paternal imprint pattern is seen on the maternal allele, which results in the
nonexpression of H19, whereas IGF2 is expressed from both parental alleles. This switching from
normally monoallelic expression to biallelic expression is known as loss of imprinting (LOI) and is
caused by IC abnormalities. As in PWS/AS, an IC abnormality prevents the resetting of imprinting in
the maternal germline and explains the observation that the affected individuals are usually born to
carrier mothers in familial cases. The same explanation can be applied to the observation that in BWS
patients with balanced rearrangements involving 11p15; the rearrangements are usually maternally
inherited. A disruption/mutation of the IC has occurred in the rearrangement process, thus preventing
the resetting of imprinting in the maternal germline.
In addition to these abnormalities involving 11p15, other not yet well-defined mechanisms or
genetic loci might also cause the BWS phenotype.
Laboratory diagnostic approaches for BWS include cytogenetic analysis to rule out an 11p15
abnormality, UPD study for the 11p15 region, mutation analysis of the CDKNIC gene, and methylation
study of IGF2, H19, and KCNQ1OT1. A recent study reported that by analyzing the methylation
status of the KCNQ1OT and H19 genes in leukocytes, over 70% of the 97 patients could be diagnosed
(121). Of all cases with abnormal methylation, 80% involved the promoter region of the KCNQ1OT
gene and 20% the H19 gene.
Cancer
Paraganglioma
A type of non-childhood tumor, paraganglioma (PGL), of the head and neck (glomus tumor) has
been mapped to chromosome 11 at two distinct loci, 11q23 and 11q13.1, by linkage analysis
(122,123). Approximately 30% of cases are familial. Mutation in SDHD, a gene mapped to 11q23
that encodes a mitochondrial respiratory chain protein, has recently been reported in families with
paraganglioma (124–126). Inheritance of PGL is autosomal dominant, with both males and females
affected. However, transmission is almost exclusively through the father (122,127,128). Only male
gene carriers will have affected offspring. The disease is not observed in the offspring of affected
females until subsequent generations, when transmission of the gene through a male carrier has
occurred. These observations suggest genomic imprinting. However, expression of SDHD is biallelic;
that is, it is expressed from both maternal and paternal alleles, in all tissues studied to date
(lymphoblastoid cell lines, adult brain, fetal brain and kidney) (124). Therefore, the mechanism for
the observed genomic imprinting inheritance pattern of this tumor is as yet uncertain. It remains
possible that imprinting of SDHD is tissue-specific and might be restricted to the carotid body, the
most common tumor site of PGL, and other paraganglionic cells.