Changes in an inherited ring (22) due to meiotic recombination? Implications for genetic counseling

At least 60 cases of r(22) have been reported to date [Schinzel, 2001]. Individuals with r(22) have a similar phenotype to individuals with deletions of the terminal portion of chromosome 22 [Jeffries et al., 2005]. In a study of 32 cases of telomeric 22q13 deletions resulting from rings, simple deletions, and translocations, Luciani et al. [2003] found no gross phenotypic differences between the 22q13 deletion and the r(22) syndromes with similarly sized deletions. Behavioral disorders were a constant feature and increased in severity with age. Patients with simple 22q13 terminal deletion had a general tendency to overgrowth, while the patients with a ring 22 often showed growth failure. In a review, Kosztolanyi et al. [1991] approximated the incidence of an inherited ring chromosome at 1% of all clinically identified ring chromosomes [Kosztolanyi et al., 1991]. Among the 32 inherited ring chromosomes, the phenotype of the offspring was similar to the parent in half the cases, the offspring were described as more severely affected than their parents in about one third of cases, and in the remainder the offspring was more mildly affected than the parent. These rare reported inherited ring cases with variable phenotypic outcome ranging from normal to severe have significant counseling implications. Inherited ring chromosome mosaicism has been reported in at least 11 families, and has been interpreted as inheritance of a inherently unstable chromosome destined to ring formation in multiple generations. In two cases of inherited mosaicism for r(19) [Flejter et al., 1996; Speevak et al., 2003] it was suggested that ring opening was responsible for the normal cell line, and some in vitro evidence suggested that this could occur. In both these cases telomeric sequences were present in the rings. Phenotypic variability between parents and offspring in the case of an inherited ring has been interpreted as the result of differences in the level of mosaicism or changes in the content of the ring chromosome itself due to mitotic instability. The strong maternal predominance among inherited rings [Kosztolanyi et al., 1991] appears to be due to the infertility of most male, but not female, ring carriers. One study of meiosis in a male carrier of a r(21) demonstrated failure of pairing of the ring, with subsequent breakdown of spermatogenesis and azoospermia [Dallapiccola et al., 1986]. The same study reported infertility in two other male r(21) carriers, while eight female r(21) carriers were fertile. Very few cases of inherited r(22) have been described. Two families had a normal phenotype in both parent and child [Teyssier and Moreau, 1985; Crusi and Engel, 1986]. In another family the child with mental retardation inherited the ring from a normal mosaic mother: breakpoints for the ring 22 were not described [Fryns and Van den Berghe, 1979]. An additional family [Stoll and Roth, 1983] had a 22q13 breakpoint with little missing chromosomal material as estimated only by size. The ring was reported to be mosaic in a mother with mild mental retardation and minor anomalies, in her unaffected father, and in her unaffected children. Wenger et al. [2000] describe a rare case of a child with abnormalities affecting both chromosomes 22. The child inherited a r(22) from the mother, and also had a deletion 22q11.2 on the other homolog. The mother was nonmosaic for r(22)(p13q13.3) and had learning disabilities. The child presented with microcephaly, short and narrow palpebral fissures, a prominent nose with hypoplastic alae nasi, thin fingers, a right aortic arch and an