Author: Prontera, P; Buldrini, B; Aiello, V; Rogaia, D; Mencarelli, A; Gruppioni, R; Bonfatti, A; Beltrami, N; Donti, E; Sensi, A
Date published: January 1, 2010
Familial pericentric inversions of chromosome 18 giving rise to rec dup(18q) have been reported at least in ten cases, all studied without molecular high-resolution methods (1, 2, 3, 5, 6, 8, 9). The recombination of an inversion with breakpoints in p11 and q21 mainly lead to a more severe phenotype than that observed when the breakpoint on the long arm is more distal (q23) (1,5, 8).
The phenotype of patients heterozygous for ree dup(18q) is a mixture of clinical features typical of del(18p) and dup(18q) karyotypes: developmental delay, mental retardation of various degree, facial dysmorphisms and hands and feet anomalies (5). Whereas ree dup(18p) is almost always associated with mental retardation and major malformations most probably due to monosomy 18q, since the clinical phenotype associated with duplication of the short arm is more subtle and variable.
Here we describe clinical, cytogenetic and molecular studies of a family in which the inv(18)(p11.32q22) gives rise to both recombinants distributed in three generations. Genotype-phenotype correlation and implications for genetic counselling are particularly focused on mother and son carrying the same rec dup (18q).
PATIENTS AND METHODS
The family came to our attention because of a five-year-old girl suffering from mental retardation, failure to thrive, facial dysmorphisms and umbilical hernia. Familial history revealed the presence of four cousins with mental retardation and congenital anomalies (Fig. 1).
High resolution (550 bands) cytogenetic analysis on GTG-banded metaphases and FISH studies with 18p and 18q subtelomeric probes (TeIVysion, Abbott, Abbott Park Illinois USA) were carried out on IVl, III 1-2-3-4 and 112 family members.
In particular, one of these patients (III4) was a 17-years-old boy, born at term with only bilateral cryptorchidism, who subsequently manifested mild global development delay (walking at 17 month, speech delay). At the time of our evaluation he showed short stature (155 cm, <3rd centile) macrocephaly (59.5 cm, >97th centile), facial dysmorphisms, speech delay and mild mental retardation (Fig. 1C,D). Very similar dysmorphisms but no cognitive impairment were observed in the mother (II2) (Fig. 1A,B).
Sex-mismatch array-CGH (800 Kb resolution) experiments were conducted on genomic DNA extracted from blood sample of II2 and III4 following the protocol suggested by the manufacturer (CytoChipvl, BlueGnome, Cambridge, UK). Threshold for gain and loss were set respectively at a ratio of 1.1 and 0.9, on the basis of the X and Y chromosomes profiles.
Karyotype and FISH analysis of the 5-year-old proband and mother disclosed rec dup(18p) and inv(18)(p11.32q22) respectively (Fig. 2ab), while a new recombinant rec dup(18q) was found in III4 and 112 (Fig. 2c).
The array-CGH analysis performed on this mother/son couple disclosed identical gain and loss patterns and allowed to refine the breakpoints of the deletion and duplication respectively to 18p11.32-pter and to 18q22.1-qter (Fig. 3).
Pericentric inversions have an incidence of about 0.01-0.07% in the general population. Large inversions with brief normally-oriented telomeric segments can result in high risk of recombinant unbalanced offspring, that ranges from 5-10% to 20% in inversions involving chromosome 18(2,6).
The recombination rate was considerably higher (4/15, 27%), most likely because of the high length of the inverted segment, in the large family reported here, in which also a direct transmission of ree dup(18q) from mother (II2) to son (III4) was documented for the first time in the literature.
This finding helped to extend the list of conditions in which an unaffected parent shares the autosomal imbalance with an affected child, but several known causes of discordant phenotypes in familial cases, such as imprinting effect, cryptic mosaicism and genomic rearrangements undetectable at cytogenetic level, can be ruled out in our case (3). Nevertheless, the occurrence of coincidental unknown genetic and/or epigenetic events such as the unmasking of recessive alleles or positional effects in the affected boy cannot be excluded.
Chromosomal imbalances are useful tools for genotype-phenotype correlation studies, however in recombinant chromosomes derived from pericentric inversions it should be taken into account that the phenotype is the result of both loss and gain of genetic material.
In the literature, the rec dup(18q) derived from a pericentric inversion of chromosome 18 with breakpoints in p11.2 and q22 has been reported in two unrelated female patients, one with dysmorphisms of the face and minor anomalies who died at 3 months and another with mental retardation, epilepsy, sensorineural deafness and major congenital anomalies (2, 6).
Comparison with published data indicates that some correlations between the extent of deletion and phenotype, in particular the mental development, can be drawn in cases of partial monosomy 18p. Wester et al. (10) described four patients with mental retardation and breakpoint in 18p 11.1 and three other children with breakpoint distal to 18pll.l (18pl 1.21), two of whom had a normal mental development and one a borderline mental retardation. When deletions are more distal or directly subtelomeric the prognosis shows more difficulty, because of the lack of sufficient data, even though terminal deletions of 18p are generally associated with normal or mild phenotype (3, 10, 7).
Brenk et al. (4) proposed a phenotypic map based on their own findings in four patients and on the review of published cases, suggesting that the gene USP14, which is located at 18p11.32, is a candidate for "postnatal growth retardation" and the gene DLGAP1, located at 18p11.31, for seizures. The short stature in the absence of seizures and a deletion that involves the USP14 but not the DLGAP1 locus in our patients (II2 and III4) supports the hypothesis of a role of USP14 in postnatal growth retardation (Table I).
[TABLE 3 OMITTED]
On the other hand, the 18q duplication can be relevant in mapping the Edwards syndrome phenotype. The phenotypes associated with the ree dup(18q) are commonly milder when the breakpoints lay within p11/q23 and more severe when they are in p11/q21, suggesting the presence of a critical region between q21 and q23 (1, 5, 8, 9). Studies on partial duplication of 18q indicated that there are at least two non contiguous regions responsible for the major features of Edwards syndrome: 18q12.1[arrow right] 18q21.2 and 18q22.3[arrow right]qter. The former is associated with more severe mental retardation and the latter with other aspects of the syndrome, such as growth deficiency, abnormal craniofacial profile, brachydactyly, seizures and umbilical hernias. Our findings support the hypothesis that a region critical for more severe phenotypes associated with duplications should be proximal to 18q22.1.
Notwithstanding our attempt to search for factors responsible for the different cognitive function between mother and son carrying rec dup(18q) by means of genomic techniques, they remain unknown and worthy of further investigations. At present, this observation leaves unsolved the matter of prognostic evaluation in similar cases so it should be taken into account particularly when genetic counselling precedes or follows prenatal diagnosis.
We thank Mrs. Salwa Pecorelli for expert English review of the manuscript.
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BY P. PRONTERA1, B. BULDRINI1, V. AIELLO2, D. ROGAIA 1, A. MENCARELLI1, R. GRUPPIONI2, A. BONFATTI2, N. BELTRAMI2, E. DONTI1 AND A. SENSI2.
(1) Medical Genetics Unit, University of Perugia, Perugia, Italy.
(2) Medical Genetics Unit, University and General Hospital of Ferrara, Ferrara, Italy.
Prontera and Buldrini contributed equally to this work.
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Paolo Prontera, MD
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