Proximal 10q duplication in a child with severe central hypotonia characterized by array-comparative genomic hybridization: A case report and review of the literature.

Proximal 10q duplication is a well-defined but rare genetic syndrome. Duplication of proximal segments of the long arm of chromosome 10 results in a pattern of malformations, which are distinct from those of the more common distal 10q trisomy syndrome. The present study describes the case of a boy with phenotypic abnormalities (severe central hypotonia, mild ataxia, moderate developmental delay and mild dysmorphic features), due to duplication of chromosome region, 10q11.21→q11.22, which was characterized by the array-comparative genomic hybridization (CGH) technique. The phenotypic findings were compared with those in eight additional similar published cases. Major similarities have emerged, suggesting a likely minimal critical region. However, only detailed characterization of additional cases may provide firm conclusions.

De novo 393 kb microdeletion of 7p11.2 characterized by aCGH in a boy with psychomotor retardation and dysmorphic features.

We report on a 27 month old boy presenting with psychomotor delay and dysmorphic features, mainly mild facial asymmetry, prominent cup-shaped ears, long eyelashes, open mouth appearance and slight abnormalities of the hands and feet. Array comparative genomic hybridization revealed a 393 kb microdeletion in 7p11.2. We discuss the possible involvement of CHCHD2, GBAS, MRPS17, SEPT14 and PSPH on our patient's phenotype. Additionally, we studied the expression of two other genes deleted in the patient, CCT6A and SUMF2, for which there is scarce data in the literature. Based on current knowledge and the de novo occurrence of this finding in our proband we presume that the aberration is likely to be pathogenic in our case. However, a single gene disorder, elsewhere in the genome or in this very region cannot be ruled out. Further elucidation of the properties of this chromosomal region, as well as of the role of the genes involved will be needed in order to draw safe conclusions regarding the association of the chromosomal deletion with the patient's features.

Prenatal diagnosis of two de novo 4q35-qter deletions characterized by array-CGH.

BACKGROUND: The 4q- syndrome is a well known genetic condition caused by a partial terminal or interstitial deletion in the long arm of chromosome 4. The great variability in the extent of these deletions and the possible contribution of additional genetic rearrangements, such as unbalanced translocations, lead to a wide spectrum of clinical manifestations. The majority of reports of 4q- cases are associated with large deletions identified by conventional chromosome analysis; however, the widespread clinical use of novel molecular techniques such as array comparative genomic hybridization (a-CGH) has increased the detection rate of submicroscopic chromosomal aberrations associated with 4q- phenotype. RESULTS: Herein we report two prenatal cases of 4qter deletions which presented the first with no sonographic findings and the second with brain ventriculomegaly combined with oligohydramnios. Standard karyotyping demonstrated a deletion at band q35.1 of chromosome 4 in both cases. The application of a-CGH confirmed the diagnosis and offered a precise characterization of the genetic defect. CONCLUSIONS: We provide a review of the currently available literature on the prenatal diagnostic approach of 4q- syndrome and we compare our results with other published cases. Our data suggest that the identification and the precise molecular characterization of new cases with 4q- syndrome will contribute in elucidating the genetic spectrum of this disorder.

Combined 22q11.1-q11.21 deletion with 15q11.2-q13.3 duplication identified by array-CGH in a 6 years old boy.

BACKGROUND: Deletions of chromosome 22q11 are present in over 90% of cases of DiGeorge or Velo-Cardio-Facial syndrome (DGS/VCFS). 15q11-q13 duplication is another recognized syndrome due to rearrangements of several genes, belonging to the category of imprinted genes. The phenotype of this syndrome varies but has been clearly associated with developmental delay and autistic spectrum disorders. Co-existence of the two syndromes has not been reported so far. RESULTS: Here we report a 6-year-old boy presenting growth retardation, dysmorphic features and who exhibited learning difficulties. Fluorescence in situ hybridization (FISH) analysis of the proband revealed a deletion of DiGeorge Syndrome critical region (TUPLE). Array-CGH analysis revealed an interstitial duplication of 12 Mb in size in the area 15q11.2-q13.3, combined with a 3.2 Mb deletion at region 22q11.1-q11.21. FISH analysis in the mother showed a cryptic balanced translocation between chromosome 15 and chromosome 22 (not evident by classic karyotyping). DISCUSION: The clinical manifestations could be related to both syndromes and the importance of array-CGH analysis in cases of unexplained developmental delay is emphasized. The present case further demonstrates how molecular cytogenetic techniques applied in the parents were necessary for the genetic counseling of the family.

The use of array-CGH in a cohort of Greek children with developmental delay.

BACKGROUND: The genetic diagnosis of mental retardation (MR) is difficult to establish and at present many cases remain undiagnosed and unexplained. Standard karyotyping has been used as one of the routine techniques for the last decades. The implementation of Array Comparative Genomic Hybridization (array-CGH) has enabled the analysis of copy number variants (CNVs) with high resolution. Major cohort studies attribute 11% of patients with unexplained mental retardation to clinically significant CNVs. Here we report the use of array-CGH for the first time in a Greek cohort. A total of 82 children of Greek origin with mean age 4.9 years were analysed in the present study. Patients with visible cytogenetic abnormalities ascertained by standard karyotyping as well as those with subtelomeric abnormalities determined by Multiplex Ligation-dependent Probe Amplification (MLPA) or subtelomeric FISH had been excluded. RESULTS: Fourteen CNVs were detected in the studied patients. In nine patients (11%) the chromosomal aberrations were inherited from one of the parents. One patients showed two duplications, a 550 kb duplication in 3p14.1 inherited from the father and a ~1.1 Mb duplication in (22)(q13.1q13.2) inherited from the mother. Although both parents were phenotypically normal, it cannot be excluded that the dual duplication is causative for the patient's clinical profile including dysmorphic features and severe developmental delay. Furthermore, three de novo clinically significant CNVs were detected (3.7%). There was a ~6 Mb triplication of 18q21.1 in a girl 5 years of age with moderate MR and mild dysmorphic features and a ~4.8 Mb duplication at (10)(q11.1q11.21) in a 2 years old boy with severe MR, multiple congenital anomalies, severe central hypotonia, and ataxia. Finally, in a 3 year-old girl with microcephaly and severe hypotonia a deletion in (2)(q31.2q31.3) of about ~3.9 Mb was discovered. All CNVs were confirmed by Fluorescence in situ hybridization (FISH). For the remaining 9 patients the detected CNVs (inherited duplications or deletions of 80 kb to 800 kb in size) were probably not associated with the clinical findings. CONCLUSIONS: Genomic microarrays have within the recent years proven to be a highly useful tool in the investigation of unexplained MR. The cohorts reported so far agree on an around 11% diagnostic yield of clinically significant CNVs in patients with unexplained MR. Various publicly available databases have been created for the interpretation of identified CNVs and parents are analyzed in case a rare CNV is identified in the child. We have conducted a study of Greek patients with unexplained MR and confirmed the high diagnostic value of the previous studies. It is important that the technique becomes available also in less developed countries when the cost of consumables will be reduced.

Detailed molecular and clinical investigation of a child with a partial deletion of chromosome 11 (Jacobsen syndrome).

BACKGROUND: Jacobsen syndrome (JBS) is a rare chromosomal disorder leading to multiple physical and mental impairment. This syndrome is caused by a partial deletion of chromosome 11, especially subband 11q24.1 has been proven to be involved. Clinical cases may easily escape diagnosis, however pancytopenia or thrombocytopenia may be indicative for JBS. RESULTS: We report a 7.5 years old boy presenting with speech development delay, hearing impairment and abnormal platelet function. High resolution SNP oligonucleotide microarray analysis revealed a terminal deletion of 11.4 Mb in size, in the area 11q24.1-11qter. This specific deletion encompasses around 170 genes. Other molecular techniques such as fluorescence in situ hybridization and multiplex ligation-dependent probe amplification were used to confirm the array-result. DISCUSSION: Our results suggest that the identification and detailed analysis of similar patients with abnormal platelet function and otherwise mild clinical features will contribute to identification of more patients with 11q deletion and JBS.