The phenotype of persons having mosaicism for trisomy 21/Down syndrome reflects the percentage of trisomic cells present in different tissues

Abstract

Little is known about the pathogenesis of the phenotype in individuals with trisomy 21 mosaicism and Down syndrome. The primary goal of this study was to identify factors contributing to the observed phenotypic variation by evaluating 107 individuals having trisomy 21 mosaicism. To investigate a potential "threshold" effect due to trisomic imbalance, lymphocyte and buccal mucosa nuclei were scored using FISH. Overall, buccal cells showed a significantly higher frequency of trisomy than lymphocytes (P < 0.0001). Using latent class analysis, two phenotypic classes were identified based on the clinical findings of the propositi. Patients from class 1 had significantly fewer traits and a lower percentage of trisomic cells (mean of 37.3% lymphocytes; 34.5% buccal mucosa cells) when compared to those stratified into class 2 (54.0% lymphocytes; 53.4% buccal mucosa cells). Tissue-specific influences were also detected, with buccal mucosa trisomy levels being significantly correlated with IQ (P = 0.0094; both ectodermal derivatives), while congenital heart defects were significantly correlated with lymphocytes (P = 0.0286; both mesodermal embryonic derivatives). In conclusion, allowing for the distinction of two groups, we observed variation in phenotype, associated with the percentage of trisomic cells. We also observed tissue-specific effects on phenotype. The results of this study should enable geneticists and other health care professionals to provide information regarding optimal diagnostic approaches and anticipated clinical outcomes.

FIG. 1

Evaluation of propositi with mosaicism for trisomy 21/Down syndrome using photographs. This figure shows photographs of an 11-year-old male who had trisomy for chromosome 21 noted in 20% of his lymphocytes in his diagnostic chromosomal report. The trisomy 21 levels observed at the time of his participation in this research study (at age 11) were 50% for his buccal mucosa cells and 7% for his lymphocytes. The photographs shown here are representative of those used to confirm phenotypic findings reported in medical records and by parents. The types of images requested from the families included (but were not limited to) those showing a full facial view (a); a side profile (b); a close-up view of the mid-face (c); and (d) a view of the mouth. This individual’s ears are slightly small, but normal in shape and position. He also has a mildly broad, but not flat nasal bridge; subtle epicanthal folds; and a high arched palate. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

FIG. 2

Distribution of the percentage of the cells of the proposita having trisomy for chromosome 21 in cultured lymphocytes and buccal mucosa cells. For the buccal mucosa specimens, the percentage values observed were not significantly different from random expectations. However, for the cultured lymphocytes, a significantly increased number of cases having trisomy 21 in 30% or fewer cells was observed.

FIG. 3

Distribution of clinical findings in study subjects having mosaicism compared to non-mosaic (complete) trisomy 21. Individuals with mosaic Down syndrome (n =104) presented with a range of 1–25 findings, compared to cases having complete trisomy 21 (n =54) in whom a range of 3–28 findings was noted.

FIG. 4

Comparison of the average ages of developmental milestone attainment. Individuals with mosaic Down syndrome (gray histograms) attained all milestones at a significantly later age than their chromosomally normal siblings (white histograms). However, with the exception of rolling over, speaking and drinking from a cup, there was a general trend for individuals with mosaic trisomy 21/Down syndrome to achieve milestones at an earlier age than individuals with full (complete) trisomy 21 Down syndrome (black histogram). (Bars denote standard error)

FIG. 5

Latent class analysis of individuals with mosaicism for trisomy 21 (a) without training variables (model 1) and (b) with training variables (individuals with full trisomy 21) [model 2]. a: A graphical representation of the conditional response probabilities for class 1 (squares [solid line]) and class 2 (circles [hatched line]) are shown. The traits that most clearly distinguished the two classes included hearing loss; small ears; low-set ears;cardiac anomalies; brachycephaly; and hernias.b: A graphical representation of the conditional response probabilities for both class1(squares [solid line]) and class 2 (circles [hatched line]) are shown. Under this model (which incorporated training variables) the data point curves are separated for the majority (76%) of traits studied. X-axis abbreviations: * Flat Face (flatface); Flat Nasal Bridge (flatnasal); Upslanted Eyes (upslanteye); Epicanthal Folds (epifolds); Myopia (myopia); Hearing Loss (hearing); PE Tubes (petubes); Small Ears (smallears); Low-set Ears (lowears); Frequent Ear Infections (earinfect); Protruding Tongue (ptongue); Dry Skin (dryskin); Single Transverse Palmar Crease (Palmar); Thin, or Sparse Hair (Thinhair); Hypotonia (hypotonia); Acyanotic Congenital Heart Defects (acyanotic); Presence of Cyanotic and Acyanotic Heart Defects (anyheart); Brachycephaly (brachyceph); Hyperextensibility of Joints (hyperjoint); Webbing, Short, or Broad Neck (webneck); Umbilical Hernia (hernia);GI Reflux (gireflux); Constipation (constipation); Hypothyroid (hypothyroid); Obesity (obesity). ^†Y-axis shows the probability of answering “yes” to a query regarding the presence of a particular phenotypic feature.