Recombinant Chromosome 8 Syndrome

A number sign (#) is used with this entry because the syndrome is caused by a recombinant chromosome 8 characterized by duplication of 8q22.1-qter and deletion of 8pter-p23.1. This chromosome, known as Rec(8), is derived from recombination of a parental pericentric inversion of chromosome 8, known as inv(8).

Clinical Features

Fujimoto et al. (1975) described a Hispanic girl with multiple anomalies, including tetralogy of Fallot and minor anomalies, who had an unbalanced recombinant chromosome 8 with partial duplication of 8q. The abnormal chromosome was inherited from the mother, who had a pericentric inversion: inv(8)(p23.1q22.1).

In patients with Rec(8), Gelb et al. (1991) found that tetralogy of Fallot constituted about 40% of the cardiovascular malformations and conotruncal defects about 55%. Gelb et al. (1991) suggested that the lack of an association between other chromosome 8 abnormalities and tetralogy of Fallot may mean that genes at the Rec(8) breakpoints or an interaction between genes on both arms of chromosome 8 are important.

Sujansky et al. (1993) identified 65 patients, published and unpublished, with the same chromosomal inversion described by Fujimoto et al. (1975). Most of the patients were of Hispanic descent, and all had duplication of 8q22-qter with deficiency of 8pter-p23. Sujansky et al. (1993) tabulated the frequency and evolution of phenotypic abnormalities on the basis of information on 42 patients spanning a period of 23 years. Congenital heart disease was present in 39 of the 42, and included tetralogy of Fallot, other conotruncal defects, and septal defects. Dysmorphic craniofacial features included hypertelorism and thin upper lip in all cases; anteverted nares, wide face, abnormal dentition, and abnormal hair whorl in more than 90% of cases; infraorbital creases, abnormally low-set ears, downturned mouth, low posterior hairline, and micrognathia in 80% or more of cases; and gingival hyperplasia, brachycephaly, midface hypoplasia, and thick lower lip in about 75% of cases. All had delayed development with moderate to severe mental retardation. Mild genitourinary tract malformations were found in 14 of 29, but none had evidence of compromised renal function. A conspicuous finding in most cases was a single ossification center in the sternum on radiographic analysis. Other less common skeletal features included scoliosis, pectus excavatum, and joint contractures.

Inheritance

In an analysis of 31 kindreds from Colorado and New Mexico with a rec(8) proband, Smith et al. (1987) estimated that an inv(8) carrier parent has a 6.2% risk of having a child with the recombinant 8 dup(q) chromosome. The transmission rate was significantly higher for carrier mothers (59%) than for carrier fathers (42%).

Cytogenetics

Smith et al. (1987) stated that the Hispanic inv(8) encompasses 74% of chromosome 8. The resultant recombinant chromosome 8, dup(q), has a duplication of the distal segment of 8q22.1-qter and a deficiency of the distal end of 8pter-p23.1. The distal segments of the breakpoints comprise 1.59% and 0.44%, respectively, of the haploid autosomal length of inv(8), yielding small enough trisomy and monosomy of these segments to allow viability. The alternative recombinant chromosome, dup(p), has never been observed, suggesting is it lethal.

Stevens et al. (2010) reported a 2-year-old boy with multiple congenital cardiac malformations, dysmorphic facies, and severe mental retardation associated with a heterozygous complex chromosome 8 consisting of a 16.9-Mb deletion of 8pter-p22 and a 21.7-Mb duplication of 8q24.13-qter. Each segment included about 150 genes. Molecular analysis of the patient's mother showed a heterozygous balanced 3-way translocation t(8;11;8)(p22;q22;q24.13). FISH analysis showed that region 8pter-8p22 was translocated to 11q; 11qter-11q22 was translocated to 8q; and 8qter-8q24.13 was translocated to 8p. These findings indicated that crossing-over in maternal meiosis led to a recombinant chromosome 8 with material from the q-arm on both ends and a deletion of part of the p-arm. This molecular mechanism was distinct from the usual mechanism of the pericentric inv(8) chromosome in San Luis Valley syndrome. Although the cytogenetics were slightly different, this patient had clinical features overlapping those reported in San Luis Valley syndrome, including a perimembranous ventricular septal defect with inlet extension, pulmonary valve stenosis, and a secundum-type atrial septal defect. Dysmorphic features included wide face with brachycephaly, plagiocephaly, hypertelorism, long eyelashes, thin vermilion border, downturned corners of the mouth, low-set ears, broad alveolar ridges, broad tip of the nose, and long philtrum. He also had hypospadias and cryptorchidism. Stevens et al. (2010) suggested that haploinsufficiency of the GATA4 gene (600576) on chromosome 8p23 may be involved in the cardiac defects.

Molecular Genetics

In a study of the breakpoint at 8p23.1 associated with the inversion 8 chromosome found in at least 1 parent of all Rec8 syndrome individuals, Patterson et al. (1995) found that the clones contained at least the 5-prime coding region of the squalene synthase gene (FDFT1; 184420).

Graw et al. (2000) cloned, sequenced, and characterized the 8p23.1 and 8q22 breakpoints from the inversion 8 chromosome associated with Rec8 syndrome. Analysis of the breakpoint regions showed that they are highly repetitive. Of 6 kb surrounding the 8p23.1 breakpoint, 75% consisted of repetitive gene family members (including Alu, LINE, and LTR elements) and the inversion took place in a small single-copy region flanked by repetitive elements. Analysis of 3.7 kb surrounding the 8q22 breakpoint showed that it is 99% repetitive and contains multiple LTR elements, and that the 8q inversion site is within one of the LTR elements. Graw et al. (2000) noted that 8p23.1 is an unstable segment of the genome.

Population Genetics

Smith et al. (1987) noted that all affected families have been of Hispanic origin. They found that 3 kindreds, from Colorado, New Mexico, and Los Angeles, respectively, had a common ancestor who could be traced to a village in northeastern New Mexico in the late 1800s. Ethnohistorical data regarding the Spanish settlement of the southwest was consistent with a Spanish founder effect. The syndrome was estimated to be about 1.5 centuries old.

Sujansky et al. (1993) studied 36 kindreds with rec(8) syndrome in the southwestern United States. All Hispanic kindreds for which the ancestral lines were known had relatives originating from a common geographic region, i.e., southern Colorado and northern New Mexico. In Colorado, the condition was known as the 'San Luis Valley syndrome.'