Inherited Interstitial Duplications of Proximal 15q: Genotype-Phenotype Correlations

We present the cytogenetic, molecular cytogenetic, and molecular genetic results on 20 unrelated patients with an interstitial duplication of the proximal long arm of chromosome 15. Multiple probes showed that the Prader-Willi/Angelman critical region (PWACR) was included in the duplication in 4/20 patients, each ascertained with developmental delay. The duplication was also found in two affected but not in three unaffected sibs of one of these patients. All four probands had inherited their duplication from their mothers, three of whom were also affected. Two of the affected mothers also carried a maternally inherited duplication, whereas the duplication in the unaffected mother and in an unaffected grandmother was paternal in origin, raising the possibility of a parental-origin effect. The PWACR was not duplicated in the remaining 16 patients, of whom 4 were referred with developmental delay. In the 14 families for which parental samples were available, the duplication was inherited with equal frequency from a phenotypically normal parent, mother or father. Comparative genomic hybridization undertaken on two patients suggested that proximal 15q outside the PWACR was the origin of the duplicated material. The use of PWACR probes discriminates between a large group of duplications of no apparent clinical significance and a smaller group, in which a maternally derived PWACR duplication is consistently associated with developmental delay and speech difficulties but not with overt features of either Prader-Willi syndrome or Angelman syndrome.     

Characterisation of interstitial duplications and triplications of chromosome 15q11–q13

Chromosome 15 is frequently involved in the formation of structural rearrangements. We report the molecular characterisation of 16 independent interstitial duplications, including those of one individual who carried a duplication on both of her chromosomes 15, and three interstitial triplications of the Prader-Willi/Angelman syndrome critical region (PWACR). In all probands except one, the rearrangement was maternal in origin. In one family, the duplication was paternal in origin, yet appeared to segregate in a sibship of three with an abnormal phenotype that included developmental delay and a behavioural disorder. Ten duplications were familial, five de novo and one unknown. All 16 duplications, including two not visible by routine G-banding, were of an almost uniform size and shared the common deletion breakpoints of Prader-Willi syndrome and Angelman syndrome. Like deletions, the formation of duplications can occur in both male and female meiosis and involve both inter- and intrachromosomal events. This implies that at least some deletions and duplications are the reciprocal products of each other. We observed no instances of meiotic instability in the transmission of a duplication, although recombination within the PWACR occurred in two members of the same family between the normal and the duplicated chromosome 15 homologues. All three triplications arose de novo and included alleles from both maternal chromosomes 15. Triplication breakpoints were more variable and extended distally beyond the PWACR. The molecular characteristics of duplications and triplications suggest that they are formed by different mechanisms.     

A familial complex chromosome translocation resulting in duplication of 6p25

We report on a girl with psychomotor retardation, severe speech developmental delay and mild dysmorphic features. Molecular cytogenetic analysis showed that the patient was carrier of an insertion (6)(p22.5-->22.4) in chromosome 12. Analysis of the chromosomes of the mother revealed the presence of a complex chromosomal rearrangement. In addition to the insertion (6)(p22.5-->22.4) in chromosome 12 and a pericentric inversion in chromosome 12, the 6p subtelomeric region was absent in the mother. This is, to our knowledge, the smallest pure duplication of chromosome 6p as well as the smallest cryptic subtelomeric 6pter deletion thus far reported.     

A de novo 3p13 deletion induced by a complex chromosomal rearrangement combined with a pericentric inversion of chromosome,inv(3)(p13q12), and a translocation between chromosome 3 and 8, t(3;8)(q13.1;q24.2), in a child with developmental delay

A de novo complex chromosomal rearrangement is very rare but likely to be present in a child with developmental disabilities and physical alterations. A child presented in this study showed global developmental delay and some typical phenotypes. Initial karyotyping and FISH analysis in the patient showed an apparently de novo balanced translocation between chromosome 3 and 8, t(3;8)(q13.1;q24.2). Further analysis using multiplex ligation-dependent probe amplification and array-based comparative genomic hybridization revealed a cryptic microdeletion on 3p13 region. Nearly one-third of balanced rearrangements are reported to involve cryptic disruptions at breakpoints, however, the microdeletion of the proposita was present in non-translocated region of the chromosome 3. After careful reevaluation of the results, a pericentric inversion, inv(3)(p13q13.1) that induced deletion was revealed. The clinical features of developmental delay in cognition, language, and motor function and facial and physical phenotype of the proposita were similar to those found in the children with 3p13 deletion. This case shows that combined molecular cytogenetic techniques with routine karyotyping are very useful to identify subtle genomic changes associated with abnormal phenotypes.     

Neurofibromatosis pseudogene amplification underlies euchromatic cytogenetic duplications and triplications of proximal 15q

Cytogenetically visible interstitial duplications of proximal 15q, which lack the Prader-Willi Angelman critical region (PWACR) frequently segregate in families without phenotypic effect, but the nature of the extra euchromatin has remained unclear. We used comparative genome hybridisation to confirm that the extra material in a cytogenetic triplication originated from proximal 15q. A PAC clone containing sequences specific for the type-1 neurofibromatosis (NF-1) pseudogenes, which map to 15q11.2, hybridised along the length of the enlarged region between the PWACR and the centromere. Computerised measurement of the fluorescent signal from the enlarged and normal chromosomes gave an average ratio of 9.85:1, consistent with amplification. In a second family, an amplified P1–4 signal co-segregated with a cytogenetic duplication and the average ratio between amplified and normal signals in the proband was 8.22:1. Ratios in non-carrier family members and control individuals were close to unity in most cases, but significantly greater than one in at least one instance. Our results provide a novel explanation for cytogenetic variation in 15q11.2. They also suggest that NF-1 pseudogene copy number may be polymorphic in the normal population, and that high copy numbers can produce G bands which do not reflect those of the normal constitutional karyotype. Received: 7 May 1998 / Accepted: 22 July 1998     

Trisomy 1q43 syndrome: a consistent phenotype with macrocephaly, characteristic face, developmental delay and cardiac anomalies

Trisomy 1q43 syndrome: a consistent phenotype with macrocephaly, characteristic face, developmental delay and cardiac anomalies: Patients with trisomy (1)(q42-qter) present with psychomotor retardation, macrocephaly, occasional presence of facial capillary naevi, cardio-vascular anomalies and small size for gestational age. We report on a girl with the same pattern of malformations, who has pure trisomy 1 q43: duplication of the region (1) (q43) and the translocation of the terminal region of the other chromosome 1 to the derivative 1, narrowing down the critical region for the characteristic traits of severe developmental delay, macrocephaly and congenital cardiac malformations.     

Redefined genomic architecture in 15q24 directed by patient deletion/duplication breakpoint mapping

We report four new patients with a submicroscopic deletion in 15q24 manifesting developmental delay, short stature, hypotonia, digital abnormalities, joint laxity, genital abnormalities, and characteristic facial features. These clinical features are shared with six recently reported patients with a 15q24 microdeletion, supporting the notion that this is a recognizable syndrome. We describe a case of an ~2.6 Mb microduplication involving a portion of the minimal deletion critical region in a 15-year-old male with short stature, mild mental retardation, attention deficit hyperactivity disorder, Asperger syndrome, decreased joint mobility, digital abnormalities, and characteristic facial features. Some of these features are shared with a recently reported case with a 15q24 microduplication involving the minimal deletion critical region. We also report two siblings and their mother with duplication adjacent and distal to this region exhibiting mild developmental delay, hypotonia, tapering fingers, characteristic facial features, and prominent ears. The deletion and duplication breakpoints were mapped by array comparative genomic hybridization and the genomic structure in 15q24 was analyzed further. Surprisingly, in addition to the previously recognized three low-copy repeat clusters (BP1, BP2, and BP3), we identified two other paralogous low-copy repeat clusters that likely mediated the formation of alternative sized 15q24 genomic rearrangements via non-allelic homologous recombination.     

A new case of pure partial 7q duplication

We report on an 18-month-old boy conceived by assisted reproduction technology with developmental delay, hypotonia, microcephaly, frontal bossing, a mild convergent squint, malformed ears, and a short neck. Karyotype analysis revealed a de novo 7q21.1q22.3 duplication characterized by array comparative genomic hybridization (array-CGH) as a segment of 18.69 Mb. Duplications of the long arm of chromosome 7 are uncommon. There are 18 reported cases of different 7q segments with a pure duplication with no additional deletion of other chromosomes. As a consequence, duplications of chromosome 7q have been classified in 4 groups on the basis of the involved region. The present case is included in group 3 which involves interstitial duplications of different sizes. In the literature, only one case with an apparently smaller duplication of the same region has been described. Despite this, the phenotype is different. Moreover, the 2 patients share some phenotypic features, such as psychomotor delay, hypotonia, frontal bossing, short neck, and strabismus. However, the absence of physical characterization in most of the reported cases could justify the lacking phenotype-genotype correlation in patients with partial 7q duplication. Further studies using recent molecular approaches such as array-CGH might permit a more clinically useful grouping of 7q duplications.     

De novo MECP2 duplication derived from paternal germ line result in dysmorphism and developmental delay

Xq28 duplications encompassing the methyl CpG binding protein 2 (MECP2) in males exhibit a distinct phenotype, including developmental delay, facial dysmorphism, muscular hypotonia, intellectual disability, poor or absent speech, recurrent infections and early death. The vast majority of affected males inherit the MECP2 duplication from their usually asymptomatic carrier mothers. Only a few cases with Xq28 duplication originating from de novo unbalanced X/Y translocation have been reported and the paternal origin of the aberration has only been validated in three males in the related literature. Here we present a karyotypically normal male with features characteristic of the MECP2 duplication syndrome. The genome-wide SNP genotyping shows a de novo 2.26-Mb duplication from Xq28 to the terminus. The genotypes of the SNPs within the duplicated region indicated a paternal origin. Furthermore, the results of fluorescence in situ hybridization (FISH) indicated a novel Xq:Yp translocation, characterized as der(Y)t(Y;X)(p11.32;q28), which suggests an aberrant that occurred during spermatogenesis. The phenotype is compared to the previously reported cases with Xq28 duplication originated from an unbalanced X/Y translocation, and there was no specific part of the phenotype that could be contributed to the origin of parental imbalances. This report further highlights the capacity of high-molecular cytogenetic methods, such as SNP array and FISH, in the identification of submicroscopic rearrangement, structural configuration and parental origin of aberrant while in the evaluation of children with idiopathic developmental delay and intellectual disability.     

Hereditary motor and sensory neuropathy (HMSN) IA, developmental delay and autism related disorder in a boy with duplication (17)(p11.2p12)

We present a 6-year-old boy with moderate developmental delay, gait disturbance, autism related disorder and mild dysmorphic features. He was seen for evaluation of his retardation since the age of 2.8 years. At first sight, a cytogenetic analysis showed a normal 46,XY karyotype. Neurological examination at the age of 5.5 years revealed a motor and sensory polyneuropathy. A quantitative Southern blot with probes PMP22 and VAW409 specific for Charcot-Marie-Tooth type 1 (CMT1) disclosed a duplication which confirmed the diagnosis HMSN Ia. Subsequently, GTG banded metaphases were re-evaluated and a small duplication 17p was seen on retrospect. Additional FISH with probe LSISMS (Vysis) specific for the Smith-Magenis region at 17p11.2 again showed a duplication. Both parents had a normal karyotype and the duplication test for CMT1 showed normal results for both of them. The boy had a de novo 46,XY,dup(17)(p11.2p12) karyotype. The present observation confirms previous findings of mild psychomotor delay, neurobehavioural features and minor craniofacial anomalies as the major phenotypic features of dup(17)(p11.2) and dup(17)(p11.2p12); in cases of duplications comprising the PMP22 locus HMSN1 is associated. A recognizable facial phenotype emerges characterized by a broad forehead, hypertelorism, downslant of palpebral fissures, smooth philtrum, thin upper lip and ear anomalies.     

Complex rearrangement involving 9p deletion and duplication in a syndromic patient: genotype/phenotype correlation and review of the literature

We describe a 7-year-old boy with a complex rearrangement involving the whole short arm of chromosome 9 defined by means of molecular cytogenetic techniques. The rearrangement is characterized by a 18.3 Mb terminal deletion associated with the inverted duplication of the adjacent 21,5 Mb region. The patient shows developmental delay, psychomotor retardation, hypotonia. Other typical features of 9p deletion (genital disorders, midface hypoplasia, long philtrum) and of the 9p duplication (brachycephaly, down slanting palpebral fissures and bulbous nasal tip) are present. Interestingly, he does not show trigonocephaly that is the most prominent dysmorphism associated with the deletion of the short arm of chromosome 9. Patient's phenotype and the underlying flanking opposite 9p imbalances are compared with that of reported patients and the proposed critical regions for 9p deletion and 9p duplication syndromes.     

Novel chromosomal translocation t(11;9)(p15;p23) involving deletion and duplication of 9p in a girl associated with autism and mental retardation

We describe a 5-year-old girl presented with autism and mental retardation features. Conventional karyotyping revealed a novel unidirectional translocation t(11;9)(p15;p23). HumanCytoSNP-12 Chip analysis identified a 13 Mb deletion from 9p24.3 to 9p23 and a 12.5Mb duplication from 9p23 to 9p21.2. The karyotype was described as 45,XX,psu dic(11; 9)(p15;p23), which was reported for the first time here. The deleted region, extending from 9p24.3 to 9p23, overlaps with the candidate region for monosomy 9p syndrome and contains a potential autism spectrum disorders (ASD) locus. The duplication region extending from 9p23 to 9p21.2 was previously identified as a critical region for the 9p duplication syndrome. These results suggested that the apparently balanced de novo translocations could produce cryptic deletions or duplications, and the precise mapping of the abnormal area may improve clinical management.     

Mosaic normal/15q11-q13 duplication associated with developmental delay but normal phenotype.

We report a proximal duplication in the long arm of chromosome 15 (15q11-15q13) in mosaic with a normal cell line in a 4-year-old boy presenting developmental delay and history of seizures, but normal phenotype.     

The Prevalence of Chromosomal Deletions Relating to Developmental Delay and/or Intellectual Disability in Human Euploid Blastocysts

Chromosomal anomalies in human embryos produced by in vitro fertilization are very common, which include numerical (aneuploidy) and structural (deletion, duplication or others) anomalies. Our previous study indicated that chromosomal deletion(s) is the most common structural anomaly accounting for approximately 8% of euploid blastocysts. It is still unknown if these deletions in human euploid blastocysts have clinical significance. In this study, we analyzed 15 previously diagnosed euploid blastocysts that had chromosomal deletion(s) using Agilent oligonucleotide DNA microarray platform and localized the gene location in each deletion. Then, we used OMIM gene map and phenotype database to investigate if these deletions are related with some important genes that cause genetic diseases, especially developmental delay or intellectual disability. As results, we found that the detectable chromosomal deletion size with Agilent microarray is above 2.38 Mb, while the deletions observed in human blastocysts are between 11.6 to 103 Mb. With OMIM gene map and phenotype database information, we found that deletions can result in loss of 81-464 genes. Out of these genes, 34–149 genes are related with known genetic problems. Furthermore, we found that 5 out of 15 samples lost genes in the deleted region, which were related to developmental delay and/or intellectual disability. In conclusion, our data indicates that all human euploid blastocysts with chromosomal deletion(s) are abnormal and transfer of these embryos may cause birth defects and/or developmental and intellectual disabilities. Therefore, the embryos with chromosomal deletion revealed by DNA microarray should not be transferred to the patients, or further gene map and/or phenotype seeking is necessary before making a final decision.     

Microduplication 22q11.2: a description of the clinical, developmental and behavioral characteristics during childhood

Microduplication 22q11.2 is a recently discovered genomic disorder. So far, targeted research on the cognitive and behavioral characteristics of individuals with this microduplication is limited. Therefore, 11 Flemish children (3-13 years old) with a microduplication 22q 1.2 were investigated in order to describe their clinical, developmental and behavioral characteristics. We measured their general intelligence, visual-motor capacities, attention, behavioral problems and characteristics of autism. In addition, there was an interview with the parents on developmental history and we reviewed available information from other specialists. The results show that the cognitive and behavioral phenotype of the children with microduplication 22q.11.2 is very wide and heterogeneous. Some of the children have a cognitively nearly normal development whereas others are more severely affected. All children had some degree of developmental delay and some of them have an intellectual disability. The most common clinical features include congenital malformations such as heart defects and cleft lip, feeding problems, hearing impairment and facial dysmorphism. The most common non-medical problems are learning difficulties, motor impairment, attention deficits, social problems and behavioral problems. There is no correlation between the size of the duplication and the phenotype.     

Two independent chromosomal rearrangements, a very small (550 kb) duplication of the 7q subtelomeric region and an atypical 17q11.2 (NF1) microdeletion, in a girl with neurofibromatosis

Most patients with neurofibromatosis (NF1) are endowed with heterozygous mutations in the NF1 gene. Approximately 5% show an interstitial deletion of chromosome 17q11.2 (including NF1) and in most cases also a more severe phenotype. Here we report on a 7-year-old girl with classical NF1 signs, and in addition mild overgrowth (97th percentile), relatively low OFC (10th-25th percentile), facial dysmorphy, hoarse voice, and developmental delay. FISH analysis revealed a 17q11.2 microdeletion as well as an unbalanced 7p;13q translocation leading to trisomy of the 7q36.3 subtelomeric region. The patient's mother and grandmother who were phenotypically normal carried the same unbalanced translocation. The 17q11.2 microdeletion had arisen de novo. Array comparative genomic hybridization (CGH) demonstrated gain of a 550-kb segment from 7qter and loss of 2.5 Mb from 17q11.2 (an atypical NF1 microdeletion). We conclude that the patient's phenotype is caused by the atypical NF1 deletion, whereas 7q36.3 trisomy represents a subtelomeric copy number variation without phenotypic consequences. To our knowledge this is the first report that a duplication of the subtelomeric region of chromosome 7q containing functional genes (FAM62B, WDR60, and VIPR2) can be tolerated without phenotypic consequences. The 17q11.2 microdeletion (containing nine more genes than the common NF1 microdeletions) and the 7qter duplication were not accompanied by unexpected clinical features. Most likely the 7qter trisomy and the 17q11.2 microdeletion coincide by chance in our patient.     

Mosaicism for an ectopic NOR at 8pter and a complex rearrangement of chromosome 8 in a patient with severe psychomotor retardation

We describe a 3-year-old girl with severe delays in mental and motor skills, a history of generalized seizures, and subtle dysmorphic features. Conventional cytogenetics revealed a mosaic karyotype. A de novo ectopic NOR at the telomeric region of the short arm of one chromosome 8 (8ps) was found in 90% of lymphocyte and in 98% of fibroblast metaphases. A small NOR-bearing marker chromosome and a large derivative chromosome 8 without short arm satellites (der(8)) were present in the remaining cells. FISH with a probe specific for centromeres 14 and 22 labeled both the telomeric region of 8ps and the small marker centromere. Der(8) included an inverted duplication of 8p and a rearranged duplication of 8q but lacked a second centromere. A subtelomeric probe for 8p revealed a cryptic deletion in 8ps and der(8). Thus, the karyotype represents a combination of submicroscopic partial monosomy 8pter and mosaic trisomy 8.