Genomic Imprinting and Uniparental Disomy in Medicine

	PHENOTYPE-GENOTYPE CORRELATIONS IN AS					201
TABLE 2 Phenotypic Characteristics of Angelman
Syndrome Patients with Paternal UPD15 as Compared to
Deletion Cases
Features	Del(15q)mat		patUPD15
Age at diagnosis	4 3=12		7 3=12
Microcephaly	58%	(11=19)	16%	(3=19)
Height < 25th centile	32%	(6=19)	17%	(3=18)
Weight > 75th centile	20%	(4=20)	71%	(12=17)
Absence of speech	89%	(16=18)	48%	(9=19)
Seizures	82%	(18=21)	42%	(8=19)
Independent gait (year)	4 6=12		2 9=12

A recent study of 14 AS patients with UBE3A mutations attempted to identify potential phenotypic characteristics of this class of AS (Moncla et al., 1999). Consistent manifestations were psychomotor delay, a happy disposition, a hyperexcitable personality, EEG abnormalities, and mental retardation with severe speech impairment. The other main manifestations of AS, ataxia, epilepsy, and microcephaly, were either milder or absent in various combinations among the patients. In addition, myoclonus of cortical origin was frequently observed with severe myoclonic seizures. The majority of the patients were overweight. This study concluded that ataxia, myoclonus, EEG abnormalities, speech impairment, characteristic behavioral phenotype, and abnormal head circumference are attributable to a deficiency in the maternally inherited UBE3A allele (Moncla et al., 1999). Obviously, more extensive studies are needed to substantiate potential clinical differences in this class of patients.

In the category of AS with IC mutation, nine cases were compared to nine agematched AS patients caused by maternal deletions of 15q (Burger et al., 1996). All had mental retardation, delayed motor development, and absent speech. However, hypopigmentation and microcephaly were only present in one of the IC mutation patients, as opposed to seven in nine of the deletion control group. The authors suggested that IC mutations cause incomplete loss of gene function or that deletions involve also genes not subject to imprinting (Burger et al., 1996).

Recently, seven patients were reported who lacked most of the features of AS, but presented with obesity, muscular hypotonia, and mild mental retardation. Based on this clinical presentation, these patients were initially suspected of having PWS, and DNA methylation analyses of SNRPN and D15S63 were performed. To the surprise of the investigators, however, the test resulted in an AS methylation pattern, i.e., paternal-only methylation (the maternal band was faint or absent) identical to that of AS (Gillessen-Kaesbach et al., 1999). Cytogenetic studies and microsatellite analysis demonstrated apparently normal chromosomes 15 of biparental inheritance. The authors concluded that these patients have an imprinting defect and a previously unrecognized form of AS. The mild phenotype may be explained by an incomplete imprinting defect or by cellular mosaicism.

202 THE ANGELMAN SYNDROME (AS)

LABORATORY TESTS IN AS

Recommendations for these tests have been published by the American Society of Human Genetics=American College of Medical Genetics Test and Technology Transfer Committee (1996) (Anonymous 1996) and can also be found in the excellent Web article of Williams et al. in Gene Clinics (http:==www.geneclinics. org=profiles=angelman=).

The laboratory tests are as follows:

Parent-specific Methylation Status

In 80% of AS cases, there is abnormal paternal-only pattern methylation status at the SNRPN locus. There is only unmethylated DNA instead of an equal mixture of methylated and unmethylated CpG SNRPN island. This abnormal methylation could be determined using Southern blot hybridization and SNRPN probes (Glenn et al., 1996). The methylation test is also useful in the detection of PWS cases. The AS cases with paternal-only methylation could have deletions in maternal 15q11-q13, paternal UPD15, or an imprinting mutation.

Further analysis to determine the exact cause includes:

(i)DNA polymorphisms to detect UPD15. Informative microsatellite polymorphisms of chromosome 15 should be used in the DNAs of the patients and their parents to establish the origin and inheritance patterns of the polymorphic alleles.

(ii)DNA analysis by FISH. Probes D15S10 or SNRPN could be used to detect large deletions of 3–4 Mb, or other probes including UBE3A to detect smaller deletions in the imprinting center. Alternatively, the deletion analysis could be performed using the inheritance of DNA polymorphic alleles in 15q11-q13.

(iii)A careful high-resolution karyotype. This should be performed in the patients and their parents to rule out structural chromosomal rearrangements.

Mutation Analysis of UBE3A

In the 20% of cases without parental specific methylation, absence of 15q11-q13 deletion and=or UPD15 (the ‘‘3 Nos!’’), a detailed analysis of the UBE3A gene should be performed to detect point mutations. The UBE3A cDNA is 2.7 kb long and encodes an 865 amino acid predicted protein. The genomic DNA spans120 kb. These are 15 coding exons and an additional 6 to 9 exons in the 50UTR. Alternative splicing of the 50UTR accounts for several different transcripts that could be translated in more than one different protein isoforms (Yamamoto et al., 1997; Kishino et al., 1997; Vu and Hoffman, 1997; Kishino and Wagstaff, 1998). The experience to date shows that the vast majority of UBE3A mutations in AS are severe null protein truncating mutations. The potential phenotypic consequence of milder mutations is unknown.

GENETIC COUNSELING IN AS

203

GENETIC COUNSELING IN AS

The genetic counseling of parents with a child with AS depends on the cause of AS in this particular family. The cause of AS could be diagnosed after a battery of laboratory tests listed above. In about 80% of patients, the molecular mechanism of AS could be identified and therefore prenatal testing could be offered. In 20% of patients, however, the molecular mechanism could not be elucidated and therefore empiric recurrence risks are usually used. In these cases, accurate prenatal diagnosis is not possible.

The categories of known molecular mechanism include (Figure 1) the following:

De novo Deletion of Maternal 15q11-q13

This is the most common etiology of AS and accounts for 70–75% of all cases. The recurrence risk (RR) is less than 1% (Connerton-Moyer et al., 1997) and prenatal diagnosis could be offered by DNA polymorphisms in the deleted region or by FISH analysis using probes from the deleted region. These probes are usually D15S10 and SNRPN.

Mutations in the UBE3A Gene

This is the second most common cause of AS ( 5%, i.e., 20% of the ‘‘3 Nos’’ cases, no deletion, no UPD15, no methylation abnormality). If the mutation is present in the mother, the RR is 50%, the same as for an autosomal dominant disease. Other members of the mother’s family may be at risk of having affected children. The UBE3A mutations in AS are not inherited from the fathers. In the case of presumed de novo mutations, there is always the possibility of maternal mosaicism (Malzac et al., 1998; Matsuura et al., 1997; Kishino et al., 1997). Fetal diagnosis could be offered by UBE3A mutation analysis of fetal DNA.

Paternal UPD15

A small fraction, approximately 2–5% of AS patients, show paternal UPD15. The RR in future pregnancies in these cases is less than 1%. Karyotypes of patients and parents should be performed to exclude a paternally inherited Robertsonian translocation. Theoretically, UPD analysis using appropriate chromosome 15 polymorphisms could be used in fetal diagnosis.

Imprinting Mutations

These are either (a) microdeletions of the imprinting center (IC) that are between 6 and 200 kb in length, or (b) abnormal, paternal-only DNA methylation pattern (Buiting et al., 1995, 1998; Saitoh et al., 1996) and account for 2–5% of these cases. If the IC deletion is present in the asymptomatic mother, the RR is 50%. First-degree relatives of these mothers may also be at risk for children or grandchildren with AS.

204 THE ANGELMAN SYNDROME (AS)

If the IC deletion is not present in the mother, then the RR is less than 1%. Fetal diagnosis could be done using probes in the deleted region.

Structural Chromosomal Rearrangements

These are rare and account for less than 1% of AS cases (Chan et al., 1993). A careful and detailed cytogenetic analysis in the mother is required to establish the nature and the inheritance of the chromosomal rearrangement. In the de novo cases, the RR is negligible, but in the inherited cases, the RR is considerable and up to 50%. A cytogenetic analysis in fetal cells could be offered in subsequent pregnancies.

In the remaining category of 20% of AS patients, there is no detectable molecular or methylation abnormality. In these cases, no accurate RR could be given and no specific prenatal test could be offered. The empiric RR is not, however, negligible.

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Genomic Imprinting and Uniparental Disomy in Medicine: Clinical and Molecular Aspects

Eric Engel, Stylianos E. Antonarkis

Copyright # 2002 Wiley-Liss, Inc. ISBNs: 0-471-35126-1 (Hardback); 0-471-22193-7 (Electronic)

Chapter 8

The Beckwith-Wiedemann

Syndrome (BWS)

The Beckwith-Wiedemann syndrome (OMIM 130650) involves another important imprinted segment of the human genome, on the short arm of chromosome 11. The etiopathogenic mechanism of the syndrome has been intensively investigated in the last several years, but our molecular understanding is still incomplete. The current molecular pathophysiology of BWS has been reviewed recently (Maher and Reik, 2000).

In the BWS and in related oncologic problems associated with chromosomal or epigenetic alterations of 11p, one major added factor of genomic imbalance is probably an overdose of some gene products that are normally hemizygously expressed. Therefore, a deregulation and overproduction of transcripts, normally committed to monoallelic expression, along with a suppression or restriction of activity from oppositely imprinted loci seem to contribute to the phenotypes of BWS.

I. THE CLINICAL PICTURE

Features and characteristics of the BWS have been thoroughly discussed in a paper presenting a remarkable familial observation of the condition (Piussan et al., 1980). The original descriptions go back to the early 1960s (Wiedemann, 1964; Beckwith, 1963). This Exomphalos-Macroglossia-Gigantism syndrome, with a reported incidence of approximately 1 in 13,500 live births (Junien, 1992; Thorburn et al., 1970) (probably an underestimate because milder cases may be undiagnosed), is characterized by numerous growth abnormalities, including visceromegaly and other occasional features, such as hemihypertrophy, earlobe creases and pits,

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