In recent years, subtelomeric rearrangements have been identified as a major cause of mental retardation and/or malformation syndromes. So far, over 2500 subjects with mental retardation have been tested and reported of whom ∼ 5% appeared to have a subtelomeric rearrangement. In this review, the clinical aspects of each known (submicroscopic) subtelomeric deletion will be presented and the various methods available for detecting subtelomeric abnormalities will be discussed. Not only will the patients and their families benefit from a good collection and report of the various telomeric abnormalities and their clinical phenotype, but it will also give more insight into the aetiology of mental retardation and malformation syndromes.

https://jmg.bmj.com/content/jmedgenet/40/6/385.full.pdf

Telomeres: a diagnosis at the end of the chromosomes

3p deletion syndrome is a rare contiguous-gene disorder involving the loss of the telomeric portion of the short arm of chromosome 3 and characterized by developmental delay, growth retardation, and dysmorphic features. All reported cases have involved, at a minimum, the deletion of chromosome 3 telomeric to the band 3p25.3. Despite the presence of several genes in this region that are involved in neural development, a causative relationship between a particular transcript and the observed clinical manifestations has remained elusive. We have identified a child with characteristic physical features of 3p deletion syndrome and both verbal and nonverbal developmental delay who carries a de novo balanced translocation involving chromosomes 3 and 10. Fine mapping of this rearrangement demonstrates that the translocation breakpoint on chromosome 3 falls within the recently identified minimal candidate region for 3p deletion syndrome and disrupts the Contactin 4 (CNTN4) mRNA transcript at 3p26.2–3p26.3. This transcript (also known as BIG-2) is a member of the immunoglobulin super family of neuronal cell adhesion molecules involved in axon growth, guidance, and fasciculation in the central nervous system (CNS). Our results demonstrate the association of CNTN4 disruption with the 3p deletion syndrome phenotype and strongly suggest a causal relationship. These findings point to an important role for CNTN4 in normal and abnormal CNS development.

Disruption of Contactin 4 (CNTN4) Results in Developmental Delay and Other Features of 3p Deletion Syndrome

In total, 200 families were reviewed with directly transmitted, cytogenetically visible unbalanced chromosome abnormalities (UBCAs) or euchromatic variants (EVs). Both the 130 UBCA and 70 EV families were divided into three groups depending on the presence or absence of an abnormal phenotype in parents and offspring. No detectable phenotypic effect was evident in 23/130 (18%) UBCA families ascertained mostly through prenatal diagnosis (group 1). In 30/130 (23%) families, the affected proband had the same UBCA as other phenotypically normal family members (group 2). In the remaining 77/130 (59%) families, UBCAs had consistently mild consequences (group 3). In the 70 families with established EVs of 8p23.1, 9p12, 9q12, 15q11.2, and 16p11.2, no phenotypic effect was apparent in 38/70 (54%). The same EV was found in affected probands and phenotypically normal family members in 30/70 families (43%) (group 2), and an EV co-segregated with mild phenotypic anomalies in only 2/70 (3%) families (group 3). Recent evidence indicates that EVs involve copy number variation of common paralogous gene and pseudogene sequences that are polymorphic in the normal population and only become visible at the cytogenetic level when copy number is high. The average size of the deletions and duplications in all three groups of UBCAs was close to 10 Mb, and these UBCAs and EVs form the "Chromosome Anomaly Collection" at http://www.ngrl.org.uk/Wessex/collection. The continuum of severity associated with UBCAs and the variability of the genome at the sub-cytogenetic level make further close collaboration between medical and laboratory staff essential to distinguish clinically silent variation from pathogenic rearrangement.

https://jmg.bmj.com/content/jmedgenet/42/8/609.full.pdf

Directly transmitted unbalanced chromosome abnormalities and euchromatic variants

One t(14q14q), three t(15q15q), two t(21q21q), and two t(22q22q) nonmosaic, apparently balanced, de novo Robertsonian translocation cases were investigated with polymorphic markers to establish the origin of the translocated chromosomes Four cases had results indicative of an isochromosome: one t(14q14q) case with mild mental retardation and maternal uniparental disomy (UPD) for chromosome 14, one t(15q15q) case with the Prader-Willi syndrome and UPD(15), a phenotypically normal carrier of t(22q22q) with maternal UPD(22), and a phenotypically normal t(21q21q) case of paternal UPD(21) All UPD cases showed complete homozygosity throughout the involved chromosome, which is supportive of a postmeiotic origin In the remaining four cases, maternal and paternal inheritance of the involved chromosome was found, which unambiguously implies a somatic origin One t(15q15q) female had a child with a ring chromosome 15, which was also of probable postmeiotic origin as recombination between grandparental haplotypes had occurred prior to ring formation UPD might be expected to result from de novo Robertsonian translocations of meiotic origin; however, all de novo homologous translocation cases, so far reported, with UPD of chromosomes 14, 15, 21, or 22 have been isochromosomes These data provide the first direct evidence that nonmosaic Robertsonian translocations, as well as isochromosomes, are commonly the result of a mitotic exchange

A somatic origin of homologous Robertsonian translocations and isochromosomes.

Haplotype analysis was undertaken in 20 cases of 15q11-q13 deletion associated with Prader-Willi syndrome (PWS) or Angelman syndrome (AS) to determine if these deletions arose through unequal meiotic crossing over between homologous chromosomes. Of these, six cases of PWS and three of AS were informative for markers on both sides of the deletion. For four of six cases of paternal 15q11-q13 deletion (PWS), markers on both sides of the deletion breakpoints were inferred to be of the same grandparental origin, implying an intrachromosomal origin of the deletion. Although the remaining two PWS cases showed evidence of crossing over between markers flanking the deletion, this was not more frequent than expected by chance given the genetic distance between proximal and distal markers. It is therefore possible that all PWS deletions were intrachromosomal in origin with the deletion event occurring after normal meiosis I recombination. Alternatively, both sister chromatid and homologous chromosome unequal exchange during meiosis may contribute to these deletions. In contrast, all three cases of maternal 15q11-q13 deletion (AS) were associated with crossing over between flanking markers, which suggests significantly more recombination than expected by chance (p = 0.002). Therefore, there appears to be more than one mechanism which may lead to PWS/AS deletions or the resolution of recombination intermediates may differ depending on the parental origin of the deletion. Furthermore, 13 of 15 cases of 15q11-q13 duplication, triplication, or inversion duplication had a distal duplication breakpoint which differed from the common distal deletion breakpoint. The presence of at least four distal breakpoint sites in duplications indicates that the mechanisms of rearrangement may be complex and multiple repeat sequences may be involved.

https://jmg.bmj.com/content/jmedgenet/35/2/130.full.pdf

The mechanisms involved in formation of deletions and duplications of 15q11-q13.

Parental age, and how extra isochromosomes (secondary trisomy) arise.

We report on a mother and son with a 3p25-pter deletion. Both have postnatal growth retardation, mental retardation, apparently low-set or malformed ears, and telecanthus. The mother also has ptosis and multiple joint pains, while the son has a long philtrum and anteverted nares. These phenotypes are compared to those of other 3p- patients. Both patients have many manifestations previously described. The son appears to be more severely affected than the mother.

V. R. Babu

Papers

Parental age, and how extra isochromosomes (secondary trisomy) arise.

Mother and son with deletion of 3p25-pter.