Prader–Willi and Angelman syndromes: genetic counseling

We read with great interest the recent Prader–Willi syndrome (PWS) and Angelman syndrome (AS) review articles by Cassidy and Driscoll (2009)¹ and by Van Buggenhout and Fryns (2009),² respectively. We completely agree with most of the contents. However, we consider it important to point out certain comments appearing in the genetic counseling section of both articles.

Knowledge of the specific genetic cause is essential to offer genetic counseling. In the genetic counseling section of the PWS article, the authors mention that ‘deletions 15q11q13 are sporadic except in rare cases where a chromosome rearrangement is present in the father'. Next, the authors assert that ‘fathers of children with deletion should be offered chromosomal and FISH analysis of the 15q11-q13 region as the recurrence risk is significantly increased in these cases'. With this assertion it is not clear whether the authors recommend studies on fathers in those cases in which a deletion resulted from a chromosome rearrangement or in any PWS case caused by a deletion. Although chromosome rearrangements are the most infrequent genetic cause (<1%), it is important to always analyze the karyotype of patients suspected of PWS to identify chromosome 15 rearrangements, plus other chromosomal anomalies.^{3, 4} Small supernumerary marker chromosomes (sSMCs) have been reported in ∼0.3% of mentally retarded patients,⁵ and in most cases, the sSMCs could be derived from chromosome 15, resulting in a UPD.⁶ We consider it important to point out that the karyotype and FISH analyses carried out in the affected child give enough information to suspect whether the deletion comes from a chromosome rearrangement. Only in these cases are studies on fathers recommended to offer a thorough genetic counseling.

We also have certain disagreements with regard to the PWS genetic counseling in the case of a matUPD. The authors assert that ‘maternal UPD 15 is typically de novo except if a Robertsonian translocation is present in either parent, so a chromosomal analysis is indicated. If this is normal, then the father of the child should be offered a chromosomal analysis to ensure that he does not have a Robertsonian translocation'. We do not agree with this affirmation because, if the patient chromosomal analysis is normal, it must be expected that the matUPD be sporadic. It is suitable to point out two important considerations. First, as we commented above, the patient chromosomal analysis is also important to identify the presence of sSMCs that could explain some matUPD cases. Second, if a Robertsonian translocation is identified in the patient karyotype and suspected as the origin of a matUPD, then it is the mother karyotype that must be analyzed instead of the father one.

We also do not agree with the comments made by Van Buggenhout and Fryns (2009)² regarding genetic counseling in those AS cases caused by a 15q11q13 deletion or by paternal UPD 15 (patUPD 15). Maternal 15q11q13 deletion or patUPD 15 could be considered de novo if a chromosome 15 rearrangement is not identified analyzing the patient's karyotype.

In those confirmed imprinting defect (ID) cases, an imprinting center (IC) quantitative analysis must be carried out to identify a possible IC deletion as the cause of ID.^{7, 8} These deletions could be sporadic or inherited from the father, who will carry the deletion on his maternal chromosome in the case of PWS, and from the mother who will carry the deletion on her paternal chromosome in the case of AS. As the IC region deleted in PWS corresponds to the SNRPN promoter region, the father analysis in these cases is as easy as performing the methylation test. If the father carries the deletion, he will show an abnormal methylation pattern (AS like) with a 50% recurrence risk. The methylation test is not useful to identify the IC deletion in AS patients' mothers, as the deleted IC region in these cases does not correspond to the SNRPN promoter region. In such PWS and AS IC deletion cases, familial studies are needed to confirm whether the IC deletion is a de novo event in the parent or if it is inherited from grandparents. It is important to note also the possibility of a grandparent being a mosaic germline carrier of the IC deletion. Thus, the PWS patient's uncles and the AS patient's aunts must be always warned about the possibility of having affected descendants if they are also carriers of the IC deletion. In the same context, the PWS patient's aunts and AS patient's uncles could also be carriers of the IC deletion, although they will not have affected descendants. However, the IC deletion could be transmitted to their next generations, who must be offered genetic counseling. The PWS patient's male cousins and the AS patient's female cousins will have a 50% recurrence risk if they have inherited the IC deletion from his mother or her father, respectively.

Finally, we want to emphasize that prenatal diagnosis is recommended to rule out a possible germ line mosaic carrier of a 15q11q13 deletion^{9, 10} or IC deletion in the case of PWS and AS, so as to rule out a UBE3A mutation in the case of AS.

As cytogenetic and genetic specialists, we go into these comments and considerations in depth, as the review articles have an important impact in the clinical and genetic community and the contents must be of as much help as possible.