The Influence of trisomy 21 on facial form and variability

Abstract

Triplication of chromosome 21 (trisomy 21) results in Down syndrome (DS), the most common live-born human aneuploidy. Individuals with DS have a unique facial appearance that can include form changes and altered variability. Using 3D photogrammatic images, 3D coordinate locations of 20 anatomical landmarks, and Euclidean Distance Matrix Analysis methods, we quantitatively test the hypothesis that children with DS (n = 55) exhibit facial form and variance differences relative to two different age-matched (4-12 years) control samples of euploid individuals: biological siblings of individuals with DS (n = 55) and euploid individuals without a sibling with DS (n = 55). Approximately 36% of measurements differ significantly between DS and DS-sibling samples, whereas 46% differ significantly between DS and unrelated control samples. Nearly 14% of measurements differ significantly in variance between DS and DS sibling samples, while 18% of measurements differ significantly in variance between DS and unrelated euploid control samples. Of those measures that showed a significant difference in variance, all were relatively increased in the sample of DS individuals. These results indicate that faces of children with DS are quantitatively more similar to their siblings than to unrelated euploid individuals and exhibit consistent, but slightly increased variation with most individuals falling within the range of normal variation established by euploid samples. These observations provide indirect evidence of the strength of the genetic underpinnings of the resemblance between relatives and the resistance of craniofacial development to genetic perturbations caused by trisomy 21, while underscoring the complexity of the genotype-phenotype map.

Keywords: Down syndrome; Euclidean Distance Matrix Analysis (EDMA); gene-dosage imbalance; human facial variation; morphometric.

© 2017 Wiley Periodicals, Inc.

Figures

Figure. 1

Diagram of how morphological differences are attributed to the effects of trisomy 21 and genetic relatedness (or lack thereof) among the Down syndrome (DS), Down syndrome sibling (DSsib), and unrelated euploid (EU) samples. A diagram of differences from two sample comparisons of the DS sample compared to DSsibs (left) and DS compared to EU (right) are shown. The DS sample is common to each two-sample analysis. Significant measurements are divided into those that overlap among two-sample comparisons and those that do not. Homologous significant measurements from each two-sample comparison that included the DS sample are attributed to the effects of trisomy 21 on facial morphology. These corresponding differences were subtracted to remove the effects of DS on facial morphology and to explore morphological similarity between DSsibs, who share approximately 50% of alleles, and unrelated EU individuals. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552-4833.

Figure. 2

Facial form differences between Down syndrome (DS), DS sibling (DSsib), and unrelated euploid (EU) samples. A) Linear distances (LDs) that significantly differ between the DS and DSsib samples (69/190 or 36%). The LDs are all 7–19% smaller in the DS sample relative to the DSsib sample. B) The LDs that significantly differ between the DS sample and the EU sample (88/190 or 46%) are shown. All LDs are 6–18% smaller in the DS sample relative to the EU sample. C) The LD that differs significantly between the DSsib sample and the EU sample (1/190 or http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552-4833.

Figure 3

Principal coordinate analysis plot of the first two principal axes (PCs) for the Down syndrome (DS), Down syndrome siblings (DSsibs), and unrelated euploid (EU) samples and morphological differences associated with each PC. PCs 1 and 2 explain the majority of facial variation among samples (59.95%). Although samples overlap, much of the DS sample (circles, solid outline) is found along the negative end of PC1 relative to the euploid samples (DSsibs depicted as squares and dotted outline; EU depicted as triangles and dashed outline). Along both PCs the sample outlines suggest that the range of formspace occupied by the DS sample is larger than the two euploid samples. The range of formspace occupied by the two euploid samples overlaps and is similar. Linear distances that are strongly correlated with the negative and positive ends of the PC axes are depicted on faces. Facial images shown have been modified to remove identifiable features. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552-4833.

Figure 4

Differences in facial variance between Down syndrome (DS), Down syndrome sibling (DSsib), and unrelated euploid (EU) samples. A) Linear distances (LDs) with variances that significantly differ (27/190 or 14%) between the DS and DSsib samples. LDs depicted with solid lines have significantly higher variances in the DS sample, and LDs depicted with dashed lines have significantly higher variances in the DSsib or EU sample. B) The LDs with variances that significantly differ between the DS and EU samples (34/190 or 18%) are shown. All LDs exhibit significantly higher variance in the DS sample relative to the EU sample (depicted as solid lines). C) The LDs with variances that significantly differ between the DSsib and the EU samples (10/190 or 5%) are shown. The LDs depicted with solid lines have significantly higher variances in the DSsib sample, and LDs depicted with dashed lines have significantly higher variances in the EU sample. D) For the DS and DSsib comparison 8 significant LDs remain after subtracting 19 LDs that were common to A and B and attributed to the effects of trisomy 21 (see Fig. 3). E) For the DS and EU comparison 15 significant LDs remain after subtracting 19 LDs that were common to A and B and attributed to the effects of trisomy 21. Facial images shown have been modified to remove identifiable features. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552-4833.

Figure 5

Model of differences in distribution of facial measures for euploid (EU) and Down syndrome (DS) populations. The EU (solid) and DS (dotted) distributions are shown overlaid upon each other. Facial measures are represented along the y-axis. Along the x-axis each population has a mean trait value (µ), with most measures being reduced in the DS population due to impaired or reduced facial growth. The DS population is more variable as shown by the left tail of the DS distribution encapsulating most of the euploid distribution while simultaneously expanding outside of the typical EU range of variation and into a region of unique morphological variation represented by the right-side of the distribution tail – a region associated with the anatomical differences and “unique” constellation of facial phenotypic characteristics associated with DS. In the right tail of the DS distribution, those individuals just beyond the euploid range of variation may have a mild facial phenotype while those individuals further outside of the EU distribution may exhibit relatively more dysmorphology and perhaps more severe anatomical and health issues associated with the craniofacial complex.