Familial mental retardation syndrome ATR-16 due to an inherited cryptic subtelomeric translocation, t(3;16)(q29;p13.3)

Abstract

In the search for genetic causes of mental retardation, we have studied a five-generation family that includes 10 individuals in generations IV and V who are affected with mild-to-moderate mental retardation and mild, nonspecific dysmorphic features. The disease is inherited in a seemingly autosomal dominant fashion with reduced penetrance. The pedigree is unusual because of (1) its size and (2) the fact that individuals with the disease appear only in the last two generations, which is suggestive of anticipation. Standard clinical and laboratory screening protocols and extended cytogenetic analysis, including the use of high-resolution karyotyping and multiplex FISH (M-FISH), could not reveal the cause of the mental retardation. Therefore, a whole-genome scan was performed, by linkage analysis, with microsatellite markers. The phenotype was linked to chromosome 16p13.3, and, unexpectedly, a deletion of a part of 16pter was demonstrated in patients, similar to the deletion observed in patients with ATR-16 syndrome. Subsequent FISH analysis demonstrated that patients inherited a duplication of terminal 3q in addition to the deletion of 16p. FISH analysis of obligate carriers revealed that a balanced translocation between the terminal parts of 16p and 3q segregated in this family. This case reinforces the role of cryptic (cytogenetically invisible) subtelomeric translocations in mental retardation, which is estimated by others to be implicated in 5%-10% of cases.

Figure 1

Pedigree of family and haplotype analysis for markers at chromosomes 16p13.3 and 3q29. The gray bars represent chromosome 3q sequences; the white bars, 16p sequences.

Figure 2

Facial photograph of patient V-5. Note hypertelorism, broad nasal bridge, and down-slanting palpebral fissures but absence of specific dysmorphic features.

Figure 3

a, Balanced translocation t(3;16)(q29;p13.3) in carrier IV-4. Metaphase spread was hybridized with subtelomere probes 3p and 3q (blue), 16q (green), and 16p (red). b, Unbalanced karyotype in individual V3. Metaphase spread was hybridized with subtelomere probes 3p and 3q (blue), 16q (green), and 16p (red) show trisomy of the tip of 3q and monosomy of the tip of 16p.

Figure 4

Pachytene analysis of the quadrivalent complex of the translocated and the normal chromosomes during meiosis I. The crossover that is noticed in individual IV-4 is indicated. This recombination explains why the 3q haplotype in patient IV-4 is different from that in the other patients.

Figure 5

Retrospective partial karyotypes of carrier IV-5, showing no abnormalities on tips of chromosome 3q and 16p. The two chromosomes 3 (a and b) and 16 (c and d) and one X chromosome (e) from one of the carriers of the balanced t(3;16) after M-FISH hybridization are shown. The first column shows the inverted DAPI image, the second column the chromosomes in classification colors. Columns three to five display the individual fluorochrome channels. Chromosome 3 is labeled with a combination of Cy3, Cy3.5, and Cy5.5, chromosome 16 with a combination of FITC and Cy5. Therefore, on one of the two long arms of chromosome 3, additional bands in the FITC and Cy5 channels should be visible and, correspondingly, one of the short arms of chromosome 16 should display additional bands in the Cy3, Cy3.5, and Cy5.5 channels. However, none of these bands are visible. As an approximate measure for the resolution, an X chromosome from the same metaphase spread is shown (e). Because of the different labeling of the X chromosome (Cy3 and Cy5.5) and the Y chromosome (FITC, Cy3.5, and Cy5.5) in the M-FISH mix, additional bands are visible on the X chromosome in the FITC and Cy3.5 channels. These bands represent the first pseudoautosomal region at Xp22.3 (size 2.6 Mb small arrows) and the XY homology region at Xq21.3 (size 4 Mb large arrows). The second pseudoautosomal region at Xq28 is too small (320 kb) to be detected. High-resolution banding of chromosomes 3 and 16 (f) demonstrates that the translocation is cytogenetically invisible.