Expanding the phenotype of reciprocal 1q21.1 deletions and duplications: a case series.

BACKGROUND: Recurrent reciprocal 1q21.1 deletions and duplications have been associated with variable phenotypes. Phenotypic features described in association with 1q21.1 microdeletions include developmental delay, craniofacial dysmorphism and congenital anomalies. The 1q21.1 reciprocal duplication has been associated with macrocephaly or relative macrocephaly, frontal bossing, hypertelorism, developmental delay, intellectual disability and autism spectrum disorder. METHODS: Our study describes seven patients, who were referred to us for developmental delay/intellectual disability, dysmorphic features and, in some cases, congenital anomalies, in whom we identified 1q21.1 CNVs by array-CGH. RESULTS: Our data confirm the extreme phenotypic variability associated with 1q21.1 microdeletion and microduplication. We observed common phenotypic features, described in previous studies, but we also described, for the first time, congenital hypothyroidism in association with 1q21.1 deletion and trigonocephaly associated with 1q21.1 duplication. CONCLUSIONS: The aim of this study is to contribute to the definition of the phenotype associated with reciprocal 1q21.1 deletions and duplications.

4p16.1-p15.31 duplication and 4p terminal deletion in a 3-years old Chinese girl: Array-CGH, genotype-phenotype and neurological characterization.

BACKGROUND: Microscopically chromosome rearrangements of the short arm of chromosome 4 include the two known clinical entities: partial trisomy 4p and deletions of the Wolf-Hirschhorn critical regions 1 and 2 (WHSCR-1 and WHSCR-2, respectively), which cause cranio-facial anomalies, congenital malformations and developmental delay/intellectual disability. METHODS/RESULTS: We report on clinical findings detected in a Chinese patient with a de novo 4p16.1-p15.32 duplication in association with a subtle 4p terminal deletion of 6 Mb in size. This unusual chromosome imbalance resulted in WHS classical phenotype, while clinical manifestations of 4p trisomy were practically absent. CONCLUSION: This observation suggests the hypothesis that haploinsufficiency of sensitive dosage genes with regulatory function placed in WHS critical region, is more pathogenic than concomitant 4p duplicated segment. Additionally clinical findings in our patient confirm a variable penetrance of major malformations and neurological features in Chinese children despite of WHS critical region's deletion.

Microdeletion 2q23.3q24.1: exploring genotype-phenotype correlations.

We report a case of a 13-year-old girl with a 5.4 Mb de novo deletion, encompassing bands 2q23.3q24.1, identified by array-comparative genomic hybridization. She presented with minor facial and digital anomalies, mild developmental delay during infancy, and behavioral disorders. Few of the reported cases overlap this deletion and all only partially. We tried to compare the clinical features of the patient with the other cases, even though not all of them were molecularly characterized in detail. Considering the neuropsychiatric involvement of the proband and the clinical descriptions of other similar cases, we attempted to identify the genes more probably involved in neurological development and function in the deleted region, particularly GALNT13, KCNJ3 and NR4A2, which are expressed in neuronal cells.

Characterization of a complex rearrangement involving chromosomes 1, 4 and 8 by FISH and array-CGH.

Complex chromosomal rearrangements (CCRs) are structural aberrations involving more than two chromosomes with at least three breakpoints. CCRs can be divided into familial and de novo. Balanced CCR are extremely rare in humans and are at high risk of producing unbalanced gametes. Individuals with balanced CCR are usually phenotipically normal but report fertility problems, recurrent miscarriages or congenital anomalies in newborn offsprings as consequence of either meiotic failure or imbalanced chromosomes segregation.We describe the case of an unbalanced CCR involving chromosomes 1, 4 and 8 found in a girl with developmental delay, hexadactilia and microcephaly. The rearrangement, apparently balanced at a standard karyotype analysis and of maternal origin, was demonstrated to be unbalanced by array-CGH and FISH. In conclusion our study underlines the importance of the combined use of a quantitative technique, as array-CGH, to detect criptic segmental aneuploidies, and a qualitative tool, as FISH analysis, to physically map the localization of the chromosome segments involved, in order to realize the exact nature that underlies a chromosomal rearrangement.

14q13.1-21.1 deletion encompassing the HPE8 locus in an adolescent with intellectual disability and bilateral microphthalmia, but without holoprosencephaly.

Interstitial deletions involving 14q13.1q21.1 are rare. In the literature at least 10 cases involving this region have been described and all patients showed a phenotype within the holoprosencephaly (HPE) spectrum. Previous studies suggested the HPE8 region as a candidate locus for HPE at 14q13. We report an adolescent with a 14q13.1q21.1 deletion encompassing the HPE8 region associated with intellectual disability (ID), bilateral microphthalmia, and coloboma, without cerebral anomalies typical of HPE. Except for ocular defects (i.e., microphthalmia, coloboma) consistent with HPE-type anomalies, the minor facial dysmorphia was not suggestive for HPE and the absence of cerebral anomalies should rule out this diagnosis. The deletion of the potential HPE candidate genes NPAS3, EAPP, SNX6, and TULIP1, raises doubts about their pathologic role in determining HPE. It is likely that deletions of HPE genes are not sufficient to cause HPE, and that multiple genetic, chromosomal, and environmental factors interact to determine the variable clinical expression of HPE. This is the first case of a 14q deletion encompassing the HPE8 locus with the only features consistent with HPE-type anomalies affecting the ocular system (i.e., microphthalmia, coloboma), and without cerebral anomalies specific for HPE. The inclusion of potential HPE candidate genes in the deletion raises the question whether this patient is affected by a less severe form of HPE (HPE microform), or whether he has a new ID/MCA deletion syndrome.

Interstitial deletion of chromosome 2p15-16.1: report of two patients and critical review of current genotype-phenotype correlation.

UNLABELLED: We report two individuals with developmental delay and dysmorphic features, in whom array-based comparative genomic hybridization (array CGH) led to the identification of a 2p15p16.1 de novo deletion. In the first patient (Patient 1) a familial deletion of 6q12, inherited from her father, was also detected. In the second patient (Patient 2) in addition to the 2p15p16.1 microdeletion a de novo deletion in Xq28 was detected. Both individuals shared dysmorphic features and developmental delay with the six reported patients with a 2p15p16.1 microdeletion described in medical literature. CONCLUSION: in the first patient a 642 kb 2p16.1 deletion (from 60.604 to 61.246 Mb), and a 930 kb 6q12 familial deletion, was detected and in the second a 2.5 Mb 2p15p16.1 deletion (from 60.258 to 62.763 Mb), with a Xq28 deletion, was discovered. The common dysmorphic features and neurodevelopmental delay found in these patients are in agreement with the clinical phenotype of a microdeletion syndrome involving 2p15p16.1. Our data confirm the hypothesis suggesting that 2p15p16.1 deletion is a contiguous gene syndrome.

The first case of myoclonic epilepsy in a child with a de novo 22q11.2 microduplication.

Chromosome 22, particularly the q11.2 sub-band, has long been recognized as responsible for multiple congenital anomaly disorders. In particular, its susceptibility to subtle microdeletions or, more rarely, microduplications has been attributed to the presence of several low-copy repeats spanning the region as mediators of nonallelic homologous recombination that result in 22q11.2 rearrangements. While recent data suggest that the frequency of 22q11.2 microduplications could be approximately half of all deletions, now only 50 unrelated cases have been reported thus far. However, it is reasonable to suppose that microduplications of 22q11.2 may be largely undetected as a result of a less-distinct, unpredictable, and/or milder phenotype ranging from normal to mild learning difficulties with/without other multiple defects. We report on the first case of myoclonic epilepsy in a 10-year-old boy carrying a de novo 22q11.2 microduplication. Emphasizing that this rare association could be one of the many unrecognized aspects underlying this new emerging syndrome and once again its clinical heterogeneity, we suggest further investigation of the function of the RAB36 gene and propose that in the screening of individuals with developmental delay, minor behavioral problems mild dysmorphology and seizures, investigation of 22q11.2 microduplications should be considered.

A 12.4 Mb direct duplication in 19q12-q13 in a boy with cardiac and CNS malformations and developmental delay.

The interstitial duplication of the long arm of chromosome 19 is a rare abnormality, characterized by developmental delay and dysmorphic features, also reported in association with cardiac, urinary, and CNS malformations. We describe a new case of de novo 19q12-q13.2 duplication characterized by fluorescent in situ hybridization (FISH) and array comparative genomic hybridization (CGH) and, by reviewing the data from previous articles, we report a tentative genotype/phenotype correlation. Four previously described cases showed the same or overlapping 19q duplications and shared with our patient common dysmorphisms, psychomotor retardation, and CNS malformations. The present description of a new case of 19q12-q13.2 duplication with a molecular cytogenetic and genomic characterization adds further elements to the understanding of the impact of the genomic segment on the phenotype.

The refinement of the critical region for the 2q31.2q32.3 deletion syndrome indicates candidate genes for mental retardation and speech impairment.

Current literature provides more than 30 patients with interstitial deletions in chromosome 2q31q33. Only a few of them were studied using high-resolution methods. Among these, two patients had presented with a particular consistence of some clinical features associated to a deletion between bands q31.2 and q32.3 of chromosome 2. This clinical pattern, labeled as "2q31.2q32.3 syndrome," consists of multiple dysmorphisms, developmental delay, mental retardation and behavioural disturbances. We report an adult female patient with a 4.4 Mb deletion in the 2q31.2q32.3 region, showing facial dysmorphisms, mental retardation and absence of speech. The region overlaps with the deletion found in the two cases previously reported. The critical region points to a few genes, namely NEUROD1, ZNF804A, PDE1A, and ITGA4, which are good candidates to explain the cognitive and behavioural phenotype, as well as the severe speech impairment associated with the 2q31.2q32.3 deletion.

Array CGH defined interstitial deletion on chromosome 14: a new case.

Interstitial deletions of the long arm of chromosome 14 are relatively rare. We report a 8.5-year-old girl with dysmorphic facial features and mental retardation associated with a de novo interstitial deletion of chromosome 14. The comparison between our patient and all published patients is reviewed. The genetic investigations have allowed us to define the critical chromosomal region and to start an accurate follow-up.

Subtelomeric FISH analysis in 76 patients with syndromic developmental delay/intellectual disability.

BACKGROUND: Intellectual disability affects approximately 1 to 3% of the general population. The etiology is still poorly understood and it is estimated that one-half of the cases are due to genetic factors. Cryptic subtelomeric aberrations have been found in roughly 5 to 7% of all cases. METHODS: We performed a subtelomeric FISH analysis on 76 unrelated children with normal standard karyotype ascertained by developmental delay or intellectual disability, associated with congenital malformations, and/or facial dysmorphisms. RESULTS: Ten cryptic chromosomal anomalies have been identified in the whole cohort (13,16%), 8 in the group of patients characterized by developmental delay or intellectual disability associated with congenital malformations and facial dysmorphisms, 2 in patients with developmental delay or intellectual disability and facial dysmorphisms only. CONCLUSION: We demonstrate that a careful clinical examination is a very useful tool for pre-selection of patients for genomic analysis, clearly enhancing the chromosomal anomaly detection rate. Clinical features of most of these patients are consistent with the corresponding emerging chromosome phenotypes, pointing out these new clinical syndromes associated with specific genomic imbalances.

De novo balanced chromosome rearrangements in prenatal diagnosis.

OBJECTIVE: We surveyed the datasheets of 29 laboratories concerning prenatal diagnosis of de novo apparently balanced chromosome rearrangements to assess the involvement of specific chromosomes, the breakpoints distribution and the impact on the pregnancy outcome. METHOD: By means of a questionnaire, data on 269.371 analyses performed from 1983 to 2006 on amniotic fluid, chorionic villus and fetal blood samples were collected. RESULTS: A total of 246 balanced anomalies were detected at frequencies of 72% for reciprocal translocations, 18% for Robertsonian translocations, 7% for inversions and 3% for complex chromosome rearrangements. The total frequencies of balanced rearrangements were 0.09%, 0.08% and 0.05% on amniotic fluid, chorionic villus and fetal blood samples. CONCLUSION: A preferential involvement of chromosomes 22, 7, 21, 3, 9 and 11 and a less involvement of chromosomes X, 19, 12, 6 and 1 was observed. A nonrandom distribution of the breakpoints across chromosomes was noticed. Association in the location of recurrent breakpoints and fragile sites was observed for chromosomes 11, 7, 10 and 22, while it was not recorded for chromosome 3. The rate of pregnancy termination was about 20%, with frequencies decreasing from complex chromosomal rearrangements (33%), reciprocal translocations (24%) to inversions (11%) and Robertsonian translocations (3%).

A case of autism with an interstitial 1q deletion (1q23.3-24.2) and a de novo translocation of chromosomes 1q and 5q.

Chromosomal abnormalities may cause autism by disrupting a gene or by providing a permissive genetic environment for mutations elsewhere in the genome to become expressed as autism. We report here on a patient with an apparently balanced de novo translocation of chromosomes 1q and 5q. He presented with minor dysmorphic features and renal malformations, mental retardation, and autism. Further characterization of the chromosomal rearrangement by FISH revealed a deletion in chromosome 1 from q23.3 to q24.2 corresponding to a region of rising interest in the research of autism susceptibility genes. The array-CGH technique gave better resolution of the breakpoints and the size of the deletion was calculated to be 4.97 Mb.

Familial robertsonian 13;14 translocation with mental retardation and epilepsy.

Familial reports of a robertsonian translocation in more than two generations are rare. We report three generations (a daughter, the mother, and the mother's father) with a heterozygous, balanced robertsonian translocation t(13;14)(q11;q11). Central nervous system disease was present, but differentially expressed, in generations I and III. The daughter presented with mental delay and epilepsy, and the mother was apparently healthy, whereas the mother's father was again symptomatic, with borderline intelligence. Fluorescent in situ hybridization analysis was performed to exclude a loss or gain of chromosomal material. No uniparental disomy was present. We concluded that genetic counseling in the presence of this rearrangement was extremely difficult, independent of the affected parent being symptomatic or asymptomatic.

Clinical phenotype and molecular characterization of 6q terminal deletion syndrome: Five new cases.

Mental retardation, facial dysmorphisms, seizures, and brain abnormalities are features of 6q terminal deletions. We have ascertained five patients with 6q subtelomere deletions (four de novo, one as a result of an unbalanced translocation) and determined the size of the deletion ranging from 3 to 13 Mb. Our patients showed a recognizable phenotype including mental retardation, characteristic facial appearance, and a distinctive clinico-neuroradiological picture. Focal epilepsy with consistent electroencephalographic features and with certain brain anomalies on neuroimaging studies should suggest 6q terminal deletion. The awareness of the distinctive clinical picture will help in the diagnosis of this chromosomal abnormality.