Systematic reanalysis of partial trisomy 21 cases with or without Down syndrome suggests a small region on 21q22.13 as critical to the phenotype.
A 'Down Syndrome critical region' (DSCR) sufficient to induce the most constant phenotypes of Down syndrome (DS) had been identified by studying partial (segmental) trisomy 21 (PT21) as an interval of 0.6-8.3 Mb within human chromosome 21 (Hsa21), although its existence was later questioned. We propose an innovative, systematic reanalysis of all described PT21 cases (from 1973 to 2015). In particular, we built an integrated, comparative map from 125 cases with or without DS fulfilling stringent cytogenetic and clinical criteria. The map allowed to define or exclude as candidates for DS fine Hsa21 sequence intervals, also integrating duplication copy number variants (CNVs) data. A highly restricted DSCR (HR-DSCR) of only 34 kb on distal 21q22.13 has been identified as the minimal region whose duplication is shared by all DS subjects and is absent in all non-DS subjects. Also being spared by any duplication CNV in healthy subjects, HR-DSCR is proposed as a candidate for the typical DS features, the intellectual disability and some facial phenotypes. HR-DSCR contains no known gene and has relevant homology only to the chimpanzee genome. Searching for HR-DSCR functional loci might become a priority for understanding the fundamental genotype-phenotype relationships in DS.
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126 Bologna, BO, Italy.
Maria Chiara
MC
Pelleri
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126 Bologna, BO, Italy.
Elena
E
Cicchini
Neonatology Unit, St. Orsola-Malpighi Polyclinic, Via Massarenti 9, 40138 Bologna, BO, Italy.
Chiara
C
Locatelli
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126 Bologna, BO, Italy.
Lorenza
L
Vitale
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126 Bologna, BO, Italy.
Maria
M
Caracausi
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126 Bologna, BO, Italy.
Allison
A
Piovesan
Neonatology Unit, St. Orsola-Malpighi Polyclinic, Via Massarenti 9, 40138 Bologna, BO, Italy.
Alessandro
A
Rocca
Neonatology Unit, St. Orsola-Malpighi Polyclinic, Via Massarenti 9, 40138 Bologna, BO, Italy.
Giulia
G
Poletti
Medical Genetics Unit.
Marco
M
Seri
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126 Bologna, BO, Italy pierluigi.strippoli@unibo.it.
Pierluigi
P
Strippoli
Neonatology Unit, St. Orsola-Malpighi Polyclinic, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, BO, Italy.
Guido
G
Cocchi
D002874:Chromosome Mapping; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D004314:Down Syndrome / Q000235:genetics* / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D014314:Trisomy / Q000235:genetics* / Q000473:pathology