ABSTRACT
BACKGROUND: Autism spectrum disorders (ASD) refer to a broader group of neurobiological conditions, pervasive developmental disorders. They are characterised by a symptomatic triad associated with qualitative changes in social interactions, defect in communication abilities, and repetitive and stereotyped interests and activities. ASD is prevalent in 1 to 3 per 1000 people. Despite several arguments for a strong genetic contribution, the molecular basis of a most cases remains unexplained. About 5% of patients with autism have a chromosome abnormality visible with cytogenetic methods. The most frequent are 15q11-q13 duplication, 2q37 and 22q13.3 deletions. Many other chromosomal imbalances have been described. However, most of them remain undetectable using routine karyotype analysis, thus impeding diagnosis and genetic counselling. METHODS AND RESULTS: 29 patients presenting with syndromic ASD were investigated using a DNA microarray constructed from large insert clones spaced at approximately 1 Mb intervals across the genome. Eight clinically relevant rearrangements were identified in 8 (27.5%) patients: six deletions and two duplications. Altered segments ranged in size from 1.4 to 16 Mb (2-19 clones). No recurrent abnormality was identified. CONCLUSION: These results clearly show that array comparative genomic hybridisation should be considered to be an essential aspect of the genetic analysis of patients with syndromic ASD. Moreover, besides their importance for diagnosis and genetic counselling, they may allow the delineation of new contiguous gene syndromes associated with ASD. Finally, the detailed molecular analysis of the rearranged regions may pave the way for the identification of new ASD genes.
Subject(s)
Child Development Disorders, Pervasive/diagnosis , Chromosome Aberrations , Oligonucleotide Array Sequence Analysis/methods , Adolescent , Adult , Child , Child Development Disorders, Pervasive/genetics , Chromosomes, Human , Female , Genetic Testing/methods , Genomics/methods , Humans , Male , SyndromeABSTRACT
Deletions of the 2q37 region are associated with a recognizable pattern of MCA/MR so-called the AHO-like syndrome. Brachydactyly is a variable but characteristic feature of this clinical entity. Here we report on five cases of cytogenetically visible de novo deletions of this 2q37 chromosome region. Using FISH, we characterized at the molecular level the breakpoints of these deletions using a set of 15 BACs, PACs and YACs. In four patients, terminal deletions of variable size ranged between 6.2 and 10 Mb. The fifth patient had an interstitial deletion with an AHO-like phenotype including brachydactyly. These findings when compared to previous observations allowed us to narrow down the brachydactyly critical region between BACs RP11-585E12 and RP11-351E10. It contains HDAC4 and STK25 candidate genes loci.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 2/genetics , Fingers/abnormalities , Hand Deformities, Congenital/genetics , Adult , Child , Child, Preschool , Female , Histone Deacetylases/genetics , Humans , Male , Protein Serine-Threonine Kinases/genetics , Repressor Proteins/geneticsABSTRACT
Premature ovarian failure occurs in almost 1% of women under age 40. Molecular alterations of the FSH receptor (FSHR) have recently been described. A first homozygous mutation of the FSHR was identified in Finland. More recently, we described two new mutations of the FSHR in a woman presenting a partial FSH-resistance syndrome (patient 1). We now report new molecular alterations of the FSHR in another woman (patient 2) who presented at the age of 19 with primary amenorrhea contrasting with normal pubertal development. She had high plasma FSH, and numerous ovarian follicles up to 3 mm in size were evidenced by ultrasonography. Histological and immunohistochemical examination of ovarian biopsies revealed the presence of a normal follicular development up to the antral stage and disruption at further stages. DNA sequencing showed two heterozygous mutations: Asp224Val in the extracellular domain and Leu601Val in the third extracellular loop of FSHR. Cells transfected with expression vectors encoding the wild type or the mutated Leu601Val receptors bound hormone with similar affinity, whereas binding was barely detectable with the Asp224Val mutant. Confocal microscopy showed the latter to have an impaired targeting to the cell membrane. This was confirmed by its accumulation as a mannose-rich precursor. Adenylate cyclase stimulation by FSH of the Leu601Val mutant receptor showed a 12+/-3% residual activity, whereas in patient 1 a 24+/-4% residual activity was detected for the Arg573Cys mutant receptor. These results are in keeping with the fact that estradiol and inhibin B levels were higher in patient 1 and that stimulation with recombinant FSH did not increase follicular size, estradiol, or inhibin B levels in patient 2 in contrast to what was observed for patient 1. Thus, differences in the residual activity of mutated FSHR led to differences in the clinical, biological, and histological phenotypes of the patient.
Subject(s)
Amenorrhea/genetics , Mutation , Ovary/physiopathology , Receptors, FSH/genetics , Adenylyl Cyclases/drug effects , Adenylyl Cyclases/metabolism , Adult , Amenorrhea/drug therapy , Animals , COS Cells/drug effects , COS Cells/metabolism , Female , Follicle Stimulating Hormone/pharmacology , Follicle Stimulating Hormone/therapeutic use , Gene Silencing , Humans , Immunohistochemistry , Male , Ovary/diagnostic imaging , Ovary/pathology , Phenotype , Primary Ovarian Insufficiency/drug therapy , Primary Ovarian Insufficiency/genetics , Protein Processing, Post-Translational , Receptors, FSH/drug effects , Receptors, FSH/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Sequence Analysis , UltrasonographyABSTRACT
Recent studies have shown that cryptic unbalanced subtelomeric rearrangements contribute to a significant proportion of idiopathic syndromic mental retardation cases. Using a fluorescent genotyping based strategy, we found a 10% rate of cryptic subtelomeric rearrangements in a large series of 150 probands with severe idiopathic syndromic mental retardation and normal RHG-GTG banded karyotype. Fourteen children were found to carry deletions or duplications of one or more chromosome telomeres and two children had uniparental disomy. This study clearly shows that fluorescent genotyping is a sensitive and cost effective method that not only detects cryptic subtelomeric rearrangements but also provides a unique opportunity to detect uniparental disomies. We suggest giving consideration to systematic examination of subtelomeric regions in the diagnostic work up of patients with unexplained syndromic mental retardation.
Subject(s)
Fluorescent Dyes , Gene Rearrangement/genetics , Intellectual Disability/genetics , Telomere/genetics , Child , Chromosome Deletion , Chromosome Mapping/economics , Chromosome Mapping/methods , Chromosome Segregation/genetics , Female , Gene Duplication , Genetic Testing/methods , Genotype , Humans , In Situ Hybridization, Fluorescence/methods , Intellectual Disability/etiology , Male , Microsatellite Repeats/genetics , Pedigree , Polymorphism, Genetic/genetics , Sensitivity and Specificity , Syndrome , Uniparental Disomy/geneticsABSTRACT
Sotos syndrome is an overgrowth syndrome characterised by pre- and postnatal overgrowth, macrocephaly, advanced bone age, and typical facial features. Weaver syndrome is a closely related condition characterised by a distinctive craniofacial appearance, advanced carpal maturation, widened distal long bones, and camptodactyly. Haploinsufficiency of the NSD1 gene has recently been reported as the major cause of Sotos syndrome while point mutations accounted for a minority of cases. We looked for NSD1 deletions or mutations in 39 patients with childhood overgrowth. The series included typical Sotos patients (23/39), Sotos-like patients (lacking one major criteria, 10/39), and Weaver patients (6/39). We identified NSD1 deletions (6/33) and intragenic mutations (16/33) in Sotos syndrome patients. We also identified NSD1 intragenic mutations in 3/6 Weaver patients. We conclude therefore that NSD1 mutations account for most cases of Sotos syndrome and a significant number of Weaver syndrome cases in our series. Interestingly, mental retardation was consistently more severe in patients with NSD1 deletions. Macrocephaly and facial gestalt but not overgrowth and advanced bone age were consistently observed in Sotos syndrome patients. We suggest therefore considering macrocephaly and facial gestalt as mandatory criteria for the diagnosis of Sotos syndrome and overgrowth and advanced bone age as minor criteria.
Subject(s)
Abnormalities, Multiple/genetics , Carrier Proteins/genetics , Craniofacial Abnormalities/genetics , Developmental Disabilities/genetics , Growth Disorders/genetics , Intellectual Disability/genetics , Intracellular Signaling Peptides and Proteins , Mutation/genetics , Nuclear Proteins/genetics , Adult , Child , Child, Preschool , Chromosome Deletion , DNA Mutational Analysis , Female , Genotype , Histone Methyltransferases , Histone-Lysine N-Methyltransferase , Humans , Male , Phenotype , Physical Chromosome Mapping , SyndromeABSTRACT
To determine which regions of chromosome 21 are involved in the pathogenesis of specific features of Down syndrome, we analysed, phenotypically and molecularly, 10 patients with partial trisomy 21. Six minimal regions for 24 features were defined by genotype-phenotype correlations. Nineteen of these features could be assigned to just 2 regions: short stature, joint hyperlaxity, hypotonia, major contribution to mental retardation and 9 anomalies of the face, hand and foot to the region D21S55, or Down syndrome chromosome region (DCR), located on q22.2 or very proximal q22.3, and spanning 0.4-3 Mb; 6 facial and dermatoglyphic anomalies to the region D21S55-MX1, including the DCR and spanning a maximum of 6 Mb on q22.2 and part of q22.3. Thus, the complex phenotype that constitutes Down syndrome may in large part simply result from the overdosage of only one or a few genes within the DCR and/or region D21S55-MX1.
Subject(s)
Chromosomes, Human, Pair 21 , Down Syndrome/genetics , Adolescent , Child , Child, Preschool , Chromosome Mapping , Female , Genotype , Humans , Infant , Infant, Newborn , Karyotyping , PhenotypeABSTRACT
Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder (incidence around 1 in 106 births), characterised by a complex immunologic defects, reduced pigmentation, and presence of giant granules in many different cell types. It most likely results from defective organellar trafficking or protein sorting. The causative gene (LYST) has recently been identified and shown to be homologous to the beige locus in the mouse. CHS has always been reported associated with premature-termination-codon mutations in both alleles of LYST. We report a unique patient with CHS, who was homozygous for a stop codon in the LYST gene on chromosome 1 and who had a normal 46,XY karyotype. The mother was found to be a carrier of the mutation, whereas the father had two normal LYST alleles. Non-paternity was excluded by the analysis of microsatellite markers from different chromosomes. The results of 13 informative microsatellite markers spanning the entire chromosome 1 revealed that the proband had a maternal isodisomy of chromosome 1 encompassing the LYST mutation. The proband's clinical presentation also confirms the absence of imprinted genes on chromosome 1.
Subject(s)
Chediak-Higashi Syndrome/genetics , Chromosome Aberrations , Chromosomes, Human, Pair 1 , Homozygote , Alleles , Child , Chromosome Banding , Fathers , Female , Genes, Recessive , Genetic Markers , Humans , In Situ Hybridization, Fluorescence , Intracellular Signaling Peptides and Proteins , Male , Models, Genetic , Mothers , Pedigree , Proteins/genetics , Reverse Transcriptase Polymerase Chain Reaction , Vesicular Transport ProteinsABSTRACT
Cryptic unbalanced subtelomeric rearrangements are known to cause a significant proportion of idiopathic mental retardation in childhood. Because of the limited sensitivity of routine analyses, the cytogenetic detection of such rearrangements requires molecular techniques, namely FISH and comparative genomic hybridisation (CGH). An alternative approach consists in using genetic markers to detect segmental aneusomy. Here, we describe a new strategy based upon automated fluorescent genotyping to search for non mendelian segregation of telomeric microsatellites. A total of 29 individuals belonging to 24 unrelated families were screened and three abnormal patterns of segregation were detected (two rearrangements and one parental disomy). This study gives strong support to the view that cryptic telomeric rearrangements significantly contribute to idiopathic mental retardation and demonstrates that fluorescent genotyping is a very sensitive and cost-effective method to detect deletions, duplications and uniparental disomies.
Subject(s)
Gene Rearrangement , Genetic Testing/methods , Intellectual Disability/genetics , Telomere/genetics , Child , Chromosomes, Human, Pair 10 , Chromosomes, Human, Pair 16 , Chromosomes, Human, Pair 6 , Cytogenetic Analysis/methods , Female , Genetic Markers , Genotype , Humans , Karyotyping , Male , Monosomy , Pedigree , Translocation, GeneticABSTRACT
5-bromodeoxyuridine incorporation was studied in metaphase chromosomes from 24 breast tumour specimens, including 23 adenocarcinomas. In these 23 cases, a slow cell cycle was observed, with a long (8 h) G2 phase. This slowing of the cell cycle, which was poorly related to the degree of polyploidy, was significantly related to the number of chromosome anomalies: the cell cycle was particularly slow when many rearranged chromosome were observed. These in vitro findings during the first cell cycle cannot easily be transposed to the in vivo situation. By analogy with Fanconi anaemia, in which both chromosome lesions and a long G2 phase are detected, a DNA repair defect and/or high DNA mutagenesis might exist in breast cancer cells.
Subject(s)
Breast Neoplasms/genetics , Chromosome Aberrations/genetics , G2 Phase/physiology , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Breast Neoplasms/pathology , Bromodeoxyuridine/metabolism , Chromosome Banding , Chromosomes/metabolism , Female , Humans , Karyotyping , Time Factors , Tumor Cells, CulturedABSTRACT
We report on a young male with mental retardation, slightly upslanting palpebral fissures, strabismus, high-arched palate, retrognathia, and flat feet. Cytogenetic analysis in addition to fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH) showed the presence of a chromosome 10p11.2-->p12.2 duplication. Karyotypes of the parents were normal. Comparison of the clinical findings observed in the present patient with those observed in other reported cases with duplication 10p suggest that the presence of high arched/cleft palate and retrognathia may be related to the 10p11.2-->p12.2 duplication. Also, no critical region for the trisomy 10p syndrome has been delimited.
Subject(s)
Abnormalities, Multiple/genetics , Chromosome Aberrations , Chromosomes, Human, Pair 10/genetics , Abnormalities, Multiple/pathology , Adult , Chromosome Banding , Flatfoot , Gene Duplication , Humans , In Situ Hybridization, Fluorescence , Intellectual Disability , Karyotyping , Male , Palate/abnormalities , RetrognathiaABSTRACT
A new patient with the rare ICF syndrome (immunodeficiency, centromeric heterochromatin instability, and facial anomalies) is reported. The six patients previously reported in the literature are reviewed. The main clinical and cytogenetic characteristics of the syndrome are discussed.
Subject(s)
Abnormalities, Multiple/genetics , Centromere , Chromosome Aberrations/genetics , Chromosomes, Human, Pair 1 , Chromosomes , Face/abnormalities , Immunologic Deficiency Syndromes/congenital , Abnormalities, Multiple/immunology , Abnormalities, Multiple/pathology , Child, Preschool , Chromosome Aberrations/pathology , Chromosome Banding , Chromosome Disorders , Female , Heterochromatin , Humans , Immunologic Deficiency Syndromes/genetics , Karyotyping , Male , Phenotype , Prognosis , SyndromeABSTRACT
We report on a child with apparent Sotos syndrome (cerebral gigantism) and partial duplication of the short arm of chromosome 20 mosaicism. Trisomy 20p11.2-p12.1 was diagnosed using cytogenetic and FISH studies. The somatostatin receptor 4 (SSTR4) gene is included in the duplicated segment. This suggests that a dosage effect of this gene might be related to some of the clinical findings observed in our patient. The present observation emphasizes the importance of chromosome analysis in patients with well-delineated but sporadic conditions.
Subject(s)
Brain Diseases/genetics , Chromosomes, Human, Pair 20/genetics , Craniofacial Abnormalities/genetics , Gigantism/genetics , Mosaicism , Trisomy , Adult , Brain Diseases/diagnosis , Child, Preschool , Chromosome Mapping , Craniofacial Abnormalities/diagnosis , Female , Gigantism/diagnosis , Humans , In Situ Hybridization, Fluorescence , Infant, Newborn , Karyotyping , Male , Microsatellite Repeats , Pregnancy , SyndromeABSTRACT
Pallister-Killian syndrome is a rare disorder comprising multiple congenital anomalies, streaks of hypo(hyper)pigmentation, seizures, profound mental retardation, and the presence of an extra metacentric chromosome i(12)(p10), usually limited to skin fibroblasts. The mechanism and parental origin of the extra chromosome i(12)(p10) are unknown. Here, we present a girl with Pallister-Killian syndrome and the i(12)(p10) in 50% of cultured skin fibroblasts. Using microsatellite DNA markers of chromosome 12p, we detected 3 alleles--including 2 different alleles of maternal origin--in cultured skin fibroblasts, suggesting that the tetrasomy 12p is the result of a prezygotic event, with a nondisjunction event during maternal meiosis.
Subject(s)
Abnormalities, Multiple/genetics , Chromosomes, Human, Pair 12 , Intellectual Disability/genetics , Isochromosomes , Skin Pigmentation/genetics , Female , Genetic Markers , Humans , Infant , Microsatellite Repeats , Pedigree , SyndromeABSTRACT
A large four-generation family with Noonan syndrome (NS) and neurofibromatosis-type 1 (NF1) was studied for clinical association between the two diseases and for linkage analysis with polymorphic DNA markers of the NF1 region in 17q11.2. Nonrandom segregation between NS and NF1 phenotypes was observed. Neurofibromatosis was tightly linked to NF1 markers, whereas Noonan syndrome was found not be allelic to NF1. These results suggest that two mutations at two independent but closely linked loci are the cause of neurofibromatosis-Noonan syndrome (NF-NS) association in this family.
Subject(s)
Genetic Linkage , Neurofibromatosis 1/genetics , Noonan Syndrome/genetics , Alleles , Chromosomes, Human, Pair 17/genetics , Female , Genes, Neurofibromatosis 1/genetics , Genetic Markers , Genotype , Humans , Infant , Male , Pedigree , Phenotype , Polymorphism, GeneticABSTRACT
We report on a girl with psychomotor retardation, growth retardation, microcephaly, frontal bossing, large ears, small nose, high arched and narrow palate, short neck, and generalized hirsutism. Cytogenetic analysis in addition to fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH) showed the presence of a chromosome 7q22-->q31.3 duplication. Comparison with other reported cases shows some resemblance but insufficient to enable us to establish a definite syndrome with specific clinical manifestations. The importance in better analyzing further cases by new molecular cytogenetics techniques is raised.
Subject(s)
Chromosomes, Human, Pair 7 , Gene Duplication , Growth Disorders/diagnosis , Growth Disorders/genetics , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Child , Chromosome Banding , Chromosome Painting , Facies , Female , Hirsutism/diagnosis , Hirsutism/genetics , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Microsatellite Repeats , Nucleic Acid Hybridization , Phenotype , SyndromeABSTRACT
A cytogenetic study is reported on the lesions induced in vitro by melphalan, a currently used anticancer drug. The distribution of 2166 breakpoints shows that they do not occur at random. There is a large excess of breaks in region q1 of chromosome 9 and R bands are significantly more affected than G-band-rich segments. Furthermore, some regions of chromosomes 5, 7, 11, and 17, which are the chromosomes usually rearranged and deleted in secondary leukemias, presumably induced by such treatments, are frequently affected. It is presumed that the frequent involvement of 9q1 largely reflects preexisting monostrand breaks. The frequent breakage of chromosomes 5, 7, 11, and 17 and of R bands in general, which are known to be G-C rich, may result from the preferential methylation of the O6 of guanine by melphalan.
Subject(s)
Chromosome Aberrations/drug effects , Leukemia/genetics , Melphalan/adverse effects , Acute Disease , Cells, Cultured , Chromosome Banding , Genetic Markers , Humans , Karyotyping , Leukemia/chemically inducedABSTRACT
A monosomy 7 was first detected in a 6-month-old boy with a chronic myelomonocytic leukemia. After etoposide treatment, relapse occurred after 29 months, with transformation of the disease into an acute myeloblastic leukemia. After bone marrow transplantations, two abnormal clones were found in marrow cells: 45,XY,-7,del(12)(p11p12)(66%), and 45,XY,-7,t(3;12)(q26;p12)(33%). Several karyotypic studies performed until the terminal phase exhibited the persistence of these two clones in the same proportion, although both independently acquired additional and often similar anomalies. The clone with t(3;12) acquired der(7),der(11),der(17),der(8),der(10),-5,-20, and the clone with del(12p), del(5q),der(4),der(8),der(10),der(17),-5,-20. The anomalies in 12p12 appear to represent an important although secondary event of the neoplastic process. The other anomalies may correspond to either those of a secondary acute nonlymphocytic leukemia, since they occurred after treatment by etoposide and alkylating agents, or to the natural evolution of myelomonocytic leukemia.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 7 , Leukemia, Myelomonocytic, Chronic/genetics , Monosomy , Bone Marrow/ultrastructure , Chromosome Banding , Follow-Up Studies , Genetic Markers , Humans , Infant , Karyotyping , Leukemia, Myelomonocytic, Chronic/pathology , MaleABSTRACT
A subacute myelomonocytic leukemia was diagnosed in 28-month-old cotwins. At this age, their spontaneously dividing cells had a normal karyotype. A few months later, after treatment with 6-mercaptopurine, the following karyotypes were observed: 50,XX, +X, +13, +19, +21 in one and 51,XX, +X, +X, +10, +19, +21 in the other. After bone marrow transplantation, both relapsed although they had received high doses of chemo- and radiotherapy. One developed a clone 46,XX,del(20q), which acquired other clonal rearrangements. The other child developed two different abnormal clones, both with unbalanced rearrangement of chromosome 13. Some of these clones may correspond to immature erythroblasts. The gain of chromosomes, especially for #13, which occurred independently in the cotwins by various mechanisms and at different periods during the disease, is very striking. It may indicate the existence of a strong selective advantage for trisomic 13 cells and may be related to the genetic constitution of the patients.
Subject(s)
Diseases in Twins , Karyotyping , Leukemia, Myelomonocytic, Acute/genetics , Twins, Monozygotic , Twins , Bone Marrow Transplantation , Chromosome Aberrations , Chromosome Disorders , Chromosomes, Human, Pair 13 , Female , Humans , Infant , Leukemia, Myelomonocytic, Acute/radiotherapy , Leukemia, Myelomonocytic, Acute/therapy , Mercaptopurine/therapeutic useABSTRACT
A decrease in the protein kinase C immunoreactivity and an altered protein phosphorylation have been reported in patients with Alzheimer's disease, but discordant results have been obtained from determinations of protein kinase C activity. By assaying the calcium- and phospholipid-dependent phosphorylation of a lysine-rich histone after detergent extraction, we have determined the total protein kinase C activity in fibroblasts from patients with sporadic Alzheimer's disease, age-matched controls and young subjects. The activity was not significantly different between young and aged controls, whereas it was significantly lower (0.70 +/- 0.12 vs 1.16 +/- 0.23 nmol/min/mg protein, P less than 0.01) in the patients. The total amount of protein kinase C estimated from the binding of phorbol dibutyrate to intact cells was also significantly lower (1.70 +/- 0.41 vs 2.48 +/- 0.54 pmol/mg protein, P less than 0.01). This decrease in protein kinase C activity suggests that abnormal protein phosphorylation might play a role in the pathogenesis of the disease.
Subject(s)
Alzheimer Disease/enzymology , Fibroblasts/enzymology , Protein Kinase C/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Humans , Leukocytes/metabolism , Middle Aged , Phorbol 12,13-Dibutyrate/metabolism , PhosphorylationABSTRACT
Phenotypic and molecular analysis of individuals with partial trisomy 21 can be used to determine which regions of chromosome 21 are involved in the pathogenesis of specific features of Down's Syndrome. Using dosage analysis of 27 sequences we defined, at the molecular level, the extent of the chromosome 21 duplication in ten individuals with partial trisomy 21. Phenotype-genotype correlations led to the definition of minimal regions, the duplications of which are linked to the expression of 23 clinical features of Down's Syndrome. The D21S55 region or Down's Syndrome Chromosome Region 1 (DCR1) (1/20 of the long arm), on 21q22.2-21q22.3 proximal, is involved in four cardinal features of the disease: mental retardation, growth retardation, muscular hypotonia and joint hyperlaxity, and in eight of the 18 more common morphological anomalies of the face, hands and feet. Overlapping the DCR1, the D21S55-MX1 region or DCR2 (1/10 of the long arm), spanning 21q21.2 down to the 1/4th proximal part of 21q22.3, is involved in the features defined by the DCR1 plus congenital heart defect and five additional morphological anomalies. Thus, our results indicate that duplication of a relatively small region of chromosome 21 plays a critical role in the pathogenesis of the Down's phenotype.