Connexion

GENATLAS PHENOTYPE

last update : 18-11-2020

Symbol	TRI21
Location	21q22-q22.13
Name	trisomy 21
Other name(s)	Down syndrome
Corresponding gene	DYRK1A , RCAN1 , APP , KCNJ6 , SIM2
Other symbol(s)	T21, DS
Main clinical features	flat facial profile with upslanting palpebral fissures, speckling of iris (Brushfield's spots), small nose, open mouth with protruding tongue, small ears, brachycephaly with flat occiput short limbs and small hands with frequent single palmar crease and short 5th middle phalange, pelvis dysplasia with flaring of iliac wings hyperflexibility of the joints, hypotonia and poor Moro reflex at birth congenital heart disease in half of children (atrioventricular defect and others), hearing loss and ophtalmological problems should be assessed for ~10% of infants present with transient myeloproliferative disorder (TMD) at or shortly after birth. TMD may be a precursor to AMKL. early occurence of Alzheimer disease prenatal screening and diagnostic are improving with combined use of maternal serum and fetal ultrasound testing intrinsic disturbance of multilineage myeloid hematopoiesis in trisomy 21 at the fetal liver stage (PMID: 23045682)), and T21 itself causes multiple distinct defects in fetal liver myelo- and lymphopoiesis (PMID: 23045701))
Genetic determination	chromosomal
Prevalence	about 1 in 800 live births
Related entries	TAM, AMKLDS
Function/system disorder	multisystem/generalized
	mental retardation
Type	MCA/MR

Gene product

Name

contiguous gene syndrome with more than 400 known genes

Mechanism(s)

Chromosome rearrangement	Effect	Comments

aneuploidy	over-expression	regular trisomy 21 with a 47,+21 karyotype in about 95 percent of patients, mosaicism in 1-2 percent of patients
translocation	over-expression	unbalanced Robertsonian translocation in 3-4 percent of patients mainly 14;21 arising de novo or due to malsegregation of a familial translocation
isochromosome	over-expression	21;21 translocation or isochromosome almost all de novo
translocation	over-expression	concommitant familial translocation and meiotic 3:1 disjunction
other	over-expression	a variety of other, extremely rare rearrangements have been observed

Remark(s)

gene-expression variation in DS suggests 3 groups of genes, with group A genes being the most dosage sensitive and the most likely involved in the constant DS traits

older mothers who have babies with Down syndrome are "genetically older" than controls, who have euploid babies at the same age and telomere length attrition may be associated in some way with meiosis I and meiosis II nondisjunction of chromosome 21 and subsequent Down syndrome births at advanced maternal age (Ghosh 2010)

trisomy 21 causes increased production of haemogenic endothelial cells, haematopoietic stem cell precursors and increased colony forming potential, with significantly increased immature progenitors, leading to increased leukaemia risk (PMID: 20697343))

Genotype/Phenotype correlations

DS phenotype is thought to result of dysregulation of critical chr21 genes and associated molecular pathways: NFAT transcription factors pathway and Sonic Hedgehog pathway, and DYRK1A-mediated deregulation of REST in 4q ; acquired somatic mutations in exon 2 of hematopoietic transcription factor GATA1 have been found in individuals with Down syndrome with both transient myeloproliferative disorder and acute megakaryoblastic leukemia ; allelic variation in a RET enhancer interacts with T21 increasing the risk for HSCR ;

trisomy for synaptojanin1 in Down syndrome is functionally linked to the enlargement of early endosomes (PMID: 22511594))

apigenin is a candidate prenatal treatment for TRI21 (apigenin is a safe treatment that can rescue oxidative stress and total antioxidant capacity imbalance in human amniocytes from fetuses with Tri21) (PMID: 33098770))