Physical map of 1p36, placement of breakpoints in monosomy 1p36, and clinical characterization of the syndrome

Abstract

Monosomy 1p36 is the most common terminal deletion syndrome. This contiguous gene deletion syndrome is presumably caused by haploinsufficiency of a number of genes. We have constructed a contig of overlapping large-insert clones for the most distal 10.5 Mb of 1p36, evaluated the deletion sizes in 61 subjects with monosomy 1p36 from 60 families, and created a natural deletion panel. We found pure terminal deletions, interstitial deletions, derivative chromosomes, and more complex rearrangements. Breakpoints were "binned" into 0.5-Mb regions. Analyses revealed some clustering of breakpoints but no single common breakpoint. Determination of the parental origin showed that 60% of de novo 1p36 terminal deletions arose from the maternally inherited chromosome. Of the 61 subjects, 30 were examined systematically through a protocol at the Texas Children's Hospital General Clinical Research Center. Specifically, we report hearing evaluations, palatal and ophthalmological examinations, echocardiograms, neurological assessments, and thyroid function tests. To our knowledge, this systematic molecular and clinical characterization of monosomy 1p36 is the largest and most comprehensive study of this deletion syndrome to date. Many cytogenetically visible, apparent terminal deletions are more complex than anticipated by cytogenetics, as revealed at the molecular level by our study. Our clinical findings allow for the more accurate recognition of the syndrome and for proper medical evaluation.

Figure 1

Six subjects with 1p36 deletions. A, A boy of age 6 years 4 mo, subject 59; B, A girl of age 4 years 6 mo, subject 52; C, A boy of age 3 years 5 mo, subject 55a; D, a girl of age 10 years 11 mo, subject 55b; E, a girl of age 8 years 8 mo, subject 51; F, A girl of age 3 years 3 mo, subject 47. Note the flat nasal bridge and nose, asymmetric ears, and pointed chin.

Figure 2

Breakpoints of 60 1p36 deletion cases. The genomic sequence of the most distal 10.5 Mb of 1p36 is shown as solid horizontal lines, beginning with the terminal telomeric repeat sequences. The minimum tiling path over the region is shown below the genomic sequence as a series of shaded boxes with BAC or PAC clone names and GenBank accession numbers above and below each box, respectively. Microsatellite and other marker locations are indicated as blackened dots along the genomic sequence line. The location of each deletion breakpoint is indicated with an arrow. Dotted lines indicate regions within which a subject’s breakpoint must be located, as assessed from microsatellite and FISH analyses. Breakpoints (“B”) for interstitial and complex deletion cases are numbered in parentheses—for example, “3(B2)” refers to subject 3, breakpoint 2—to distinguish each breakpoint location, because the rearrangements have more than one breakpoint. Pink patient numbers indicate maternally derived deletions, and blue patient numbers indicate paternally derived deletions. Black patient numbers indicate those in whom the parental origin could not be determined. Five sequence gaps are shown roughly to scale from data obtained from fiber FISH experiments performed by the Wellcome Trust Sanger Institute (S. Gregory, personal communication).

Figure 3

Breakpoint locations of 60 1p36 deletions. Breakpoint clustering was plotted as a histogram of the total number of breakpoints within each 0.5-Mb bin of the terminal 10.5 Mb of 1p36. All breakpoints are included for those subjects with multiple breakpoints due to interstitial deletions or complex rearrangements.

Figure 4

Classes of 1p36 deletions. The genomic sequence of the most distal 10.5 Mb of 1p36 is depicted as an extended vertical arrow. A, The breakpoint locations of the 43 subjects with apparently pure terminal deletions are indicated on a single solid arrow. The breakpoints of the 4 interstitial deletions (B), the 10 derivative chromosomes (C), and the 3 complex rearrangements (D) are represented as individual arrows. Solid lines indicate regions of 1p36 that are not deleted. Dotted lines indicate regions of 1p36 that are deleted. Pink patient numbers indicate maternally derived deletions; blue patient numbers indicate paternally derived deletions. Black patient numbers identify those whose parental origins could not be determined. The origin of the chromosomal material (as identified by FISH) that is translocated to the end of 1p36 in the derivative chromosome cases is listed within the circle at the telomeric end of each arrow. Asterisks indicate derivative chromosomes that are not de novo in origin.

Figure 5

Gene content of critical regions within 1p36. The most distal 4.0 Mb of 1p36 is shown because the majority of critical regions are found in this segment. The known genes and full-length mRNAs are listed across the top. The telomere is at the far left of the figure. The slashes indicate a break in continuity of the distance. The names of the large-insert clones are listed as in figure 2. The approximate critical regions for the phenotypes are indicated by the horizontal colored bars.