A 6 Mb deletion in band 2q22 due to a complex chromosome rearrangement associated with severe psychomotor retardation, microcephaly and distinctive dysmorphic facial features

doi:10.1016/j.ejmg.2006.11.004

European Journal of Medical Genetics

Volume 50, Issue 2, March–April 2007, Pages 149-154

https://doi.org/10.1016/j.ejmg.2006.11.004 Get rights and content

Abstract

High-resolution analyses of complex chromosome rearrangements (CCR) have demonstrated in individuals with abnormal phenotypes that not all seemingly balanced CCRs based on G-banding are completely balanced at breakpoint level. Here we report on an apparently balanced de novo CCR involving chromosomes 2, 3 and 5 present in a 6-month-old girl. She was referred for genetic evaluation because of severe psychomotor retardation, distinctive dysmorphic features and microcephaly. A 1 Mb resolution array-CGH analysis of DNA from the patient revealed a deletion of about 6 Mb for chromosome 2. FISH analysis showed that the deletion interval found in band 2q22 mapped at the translocation breakpoint, and that the ZFHX1B gene, which is known to be involved in the Mowat–Wilson syndrome, is located within the deletion interval.

To our knowledge this is the first case of a complex chromosomal rearrangement associated with Mowat–Wilson syndrome. Our data illustrate the important role for high-resolution investigation of apparently balanced chromosome rearrangements in patients with unexplained psychomotor retardation and/or other clinical features, and should contribute to our understanding of the mechanisms involved in chromosome rearrangement.

Section snippets

Chromosome analysis

Conventional karyotyping based on GTG-banding was performed using standard methods on metaphases from peripheral blood. This analysis revealed a complex chromosomal rearrangement with three breakpoints including chromosomes 2, 3 and 5 (Fig. 1). The patients karyotype was therefore 46,XX,t(2;3;5)(q21.3;q12;q13.3). Based on G-banding analysis the translocation seemed to be balanced.

Array-CGH

Array-based comparative genomic hybridization analysis (array-CGH) was performed in DNA from peripheral blood from

Clinical description

A girl was examined at the age of 6 months because of severe psychomotor retardation. After an uneventful pregnancy and delivery, her weight at birth was 3.4 kg, her length was 64.5 cm (−1 SDS) and the head circumference was 39.5 cm (−2 SDS). Physical examination revealed microcephaly, spastic tetraparesis, strabismus, marked hypertelorism, frontal bossing, large uplifted earlobes and a broad nasal tip (Fig. 3). There were difficulties in making eye contact with her but she easily laughed. An MRI of

Discussion

Array-CGH was used to investigate a potential DNA imbalance in a patient with unexplained psychomotor retardation and dysmorphic features. Previous routine clinical cytogenetic investigation revealed an apparently balanced complex de novo 3-way translocation involving chromosomes 2, 3 and 5. Array-CGH revealed a 6 Mb deletion at band 2q22 and FISH analysis confirmed that the deletion is at the translocation breakpoint on chromosome 2. The rearrangement therefore, harbours a cryptic microdeletion

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Mowat-Wilson syndrome associated with Hirschsprung disease
2022, Journal of Pediatric Surgery Case Reports
Mowat-Wilson syndrome (MWS) is a rare autosomal dominant genetic disease caused by mutations in the zinc finger E-box binding homeobox 2 (ZEB2) gene. The syndrome is associated with Hirschsprung disease (HSCR). To investigate and report the clinical characteristics of MWS associated with HSCR and the treatment outcome of patients after radical operation for HSCR.
The clinical features and gene mutation results of a patient with MWS and HSCR diagnosed by ZEB2 genetic analysis were literature review.
The patient was female and presented abdominal distension, constipation, patent ductus arteriosus and a distinctive facial appearance, including ocular hypertelorism, prominent forehead and nasal tip, low-set ears, and uplifted earlobes. The patient was pathologically diagnosed with HSCR after undergoing laparoscopic Soave procedure at 9 months old. After surgical treatment, the defecation function returned to normal until the follow-up to 1 year and 10 months of age. A heterozygous mutation in the ZEB2 gene on chromosome 2 of the patient results in amino acid change c.244G > T (p.E82X), which is an unreported new mutation.
Gene examination should be performed in children with HSCR combined with appearance changes. c.244G > T (p.E82X) may be a new disease-related locus.
Mowat-Wilson syndrome detected by using high resolution microarray
2013, Gene
Citation Excerpt :
Large deletions (11 Mb and 5 Mb) have been reported for spasticity, and neonatal seizure disorder. Small deletions (300 kb and 700 kb) have been reported for anomalies of the corpus callosum (Table 1: Hoffer et al., 2007; Zweier et al., 2003). Regardless of deletion size, Hirschsprung disease, hypotonia, and congenital heart disease are present with varying ages of onset (Hoffer et al., 2007; Zweier et al., 2003).
Individuals with Mowat–Wilson syndrome (MWS; OMIM#235730) have characteristic facial features, a variety of congenital anomalies such as Hirschsprung disease, and intellectual disabilities caused by mutation or deletion of ZEB2 gene. This deletion or cytogenetic abnormality has been reported primarily from Europe, Australia and the United States, but not in Korea. Here we report a patient with characteristic facial features of MWS, developmental delay and spasticity. High resolution microarray analysis revealed 0.9 Mb deletion of 2q22.3 involving two genes: ZEB2 and GTDC1. This case shows the important role of high resolution microarray in patients with unexplained psychomotor retardation and/or facial dysmorphism. Knowledge about the most striking clinical signs and implementation of effective molecular tests like microarray could significantly increase the detection rate of new cases of MWS in Korea. This is the first reported case of MWS in Korea.
Balanced Reciprocal Translocations Detected at Amniocentesis
2010, Taiwanese Journal of Obstetrics and Gynecology
To present perinatal findings, modes of ascertainment and parental decision in balanced reciprocal translocations detected at amniocentesis.
Between January 1987 and August 2010, 82 cases with a simple reciprocal translocation, two cases with two separate simple reciprocal translocations and three cases with a complex chromosome rearrangement (CCR) were diagnosed by amniocentesis at Mackay Memorial Hospital, Taipei, Taiwan. The 87 cases originated from 76 families; 65 families with one case and 11 families with two cases.
In the 76 families, the main modes of ascertainment included advanced maternal age (n=38), a previous child with an unbalanced reciprocal translocation (n=11), recurrent miscarriage (n = 9), abnormal maternal serum screening results (n = 9), elective causes (n = 5), a previous child with congenital anomalies (n =2) and abnormal ultrasound findings (n = 2). In these families, there were 17 (22.4%) de novo cases including 14 simple translocations and three CCRs. Of 14 de novo cases with a simple translocation, one (7.1%) manifested a congenital malformation, which was related to an X-autosome translocation, and four (28.6%) were terminated. Of three de novo CCRs, two manifested congenital anomalies and one was terminated. In 87 cases, additional aneuploidy was noted in two cases including one inherited simple translocation with Turner syndrome, and one de novo CCR with concomitant deletions and duplication.
Balanced reciprocal translocations detected at amniocentesis may be associated with fetal anomalies in cases of concomitant aneuploidy, de novo X-autosome translocation or de novo CCR. Genetic counseling of a de novo simple reciprocal translocation at amniocentesis remains difficult because approximately one-fourth of the parents opt for termination of the pregnancy, and detailed ultrasonography and array comparative genomic hybridization are helpful for parental counseling under such circumstances.
Cytogenetic, FISH and array-CGH characterization of a complex chromosomal rearrangement carried by a mentally and language impaired patient
2009, European Journal of Medical Genetics
Citation Excerpt :
Recent literature reports evidence of cryptic CCRs appearing as simple balanced translocations [19,8] and points out among apparently balanced CCRs an increasing number of imbalances at both the underlying breakpoints and elsewhere in the genome [3,16,6,13,22,12]. Deletions, which may affect dosage sensitive genes, are the main cause of phenotypic abnormalities in these and other single cases that have been reported [26,14]. Furthermore, the severity of the phenotype seems to correlate to the gene content of the unbalanced regions and their genetic background rather than to the number and extent of the deletions [9].
We describe a patient with an abnormal phenotype and a de novo CCR consisting of a reciprocal translocation between chromosomes 1 and 15 and an insertion of an interstitial segment from chromosome 2 within chromosome 1. The CCR was studied by QFQ banding and FISH. The apparently balanced rearrangement was further investigated with array-CGH, that uncovered three cryptic deletions on chromosome 2q. By means of BAC-FISH two deletions were located at the breakpoints of the insertion, at 2q14.3 and 2q31.2, and one at 2q22.2, in the region of 2q translocated on derivative 1. Consequently, in silico analysis of the deleted regions was performed. Among deleted genes, particularly interesting seems to be CNTNAP5, encoding a member of the neurexin superfamily. The three mouse orthologues are highly expressed in adult brain tissues. We speculate that loss of CNTNAP5 might contribute to the developmental language delay of this patient, similar to CNTNAP2, another member of the same protein family, whose alterations have been recently associated with delay in the age at first word in autistic patients. At clinical patient's evaluation, a Mowat–Wilson syndrome (MWS) like appearance was noted. The disease is caused by mutation or deletion of ZEB2 gene, located in our patient 794 Kb distally to the 2q22.2 deletion, in the chromosome 2 segment inserted into the derivative 1. The loss of the gene has been excluded by the array-CGH results, but its proximity to the deleted segment and/or its insertion in a different genetic context might influence and consequently impair its expression. Our study confirms that array-CGH is a precious method to identify cryptic imbalances in CCR carriers and underlie the essential role of BAC-FISH as second step of analysis to assess the reciprocal position of the chromosomal segments involved in CCRs and the exact mapping of the imbalances.
TWIST microdeletion identified by array CGH in a patient presenting Saethre-Chotzen phenotype and a complex rearrangement involving chromosomes 2 and 7
2008, European Journal of Medical Genetics
Citation Excerpt :
Nevertheless, high resolution oligonucleotide array CGH was preferred since it allowed not only to confirm the presence of the suspected deletion but also to provide accurate information on its size and on possible other imbalances. Indeed, array CGH contributed in the last years to the study of apparently balanced rearrangements associated with abnormal phenotypes [4,8,10,11,15–18]. It demonstrated gain and/or loss of material at the breakpoints [4,8,10,18] but it also revealed additional imbalances apparently unrelated to the initial rearrangement [4,8].
Saethre–Chotzen syndrome (SCS), also known as acrocephalosyndactyly III, is an autosomal dominant hereditary disorder characterized by craniofacial and limb anomalies. SCS is generally caused by mutations in the TWIST gene, but several 7p21.3 microdeletions involving the entire gene have also been described.
The patient reported here presented with craniosynostosis, ptosis, brachydactyly and syndactyly of toes. Standard lymphocyte karyotype showed a de novo apparently balanced but complex constitution with a translocation between the short arms of chromosomes 2 and 7 and an insertion of the 7(q21.3q22) band in the short arm of the same chromosome 7. Interestingly, array CGH displayed a unique 690 kb deletion in 7p21.3 involving the TWIST gene, consistent with the phenotype.
This case illustrates the important contribution of array CGH to identification of complex chromosomal rearrangements.
Deletion of 2q222q22.3 in Mowat-Wilson Syndrome: A Case Report and Review of the Literature
2022, Journal of Pediatric Neurology

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Chromosomal imbalance letterA 6 Mb deletion in band 2q22 due to a complex chromosome rearrangement associated with severe psychomotor retardation, microcephaly and distinctive dysmorphic facial features

Abstract

Section snippets

Chromosome analysis

Array-CGH

Clinical description

Discussion

Am. J. Hum. Genet.

Eur. J. Med. Genet.

Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease

Hum. Mol. Genet.

Comparative analysis of comparative genomic hybridization microarray technologies: report of a workshop sponsored by the Wellcome Trust

Cytometry

Mowat–Wilson syndrome and mutation in the zinc finger homeo box 1B gene: a well defined clinical entity

J. Med. Genet.

DNA microarrays for comparative genomic hybridization based on DOP-PCR amplification of BAC and PAC clones

Genes Chromosomes Cancer

Chromosomal imbalance letter
A 6 Mb deletion in band 2q22 due to a complex chromosome rearrangement associated with severe psychomotor retardation, microcephaly and distinctive dysmorphic facial features