Detection of an insertion deletion of region 8q13-q21.2 in a patient with Duane syndrome: implications for mapping and cloning a Duane gene

Abstract

Duane syndrome (MIM126800) is an autosomal dominant disease responsible for 1% of all strabismus cases and has been related to a 8q12-13 contiguous gene syndrome. We report on an insertion of chromosome region 8q13-q21.2 on to band 6q25 in a patient presenting with Duane syndrome, mental retardation, and other dysmorphisms. FISH analysis using chromosome 8 radiation hybrid LIA2L indicated a concurrent deletion within the 8q rearranged region. These results were corroborated by STR-PCR analysis and FISH using YAC contig WC8.8 disclosed a deletion in 8q13. Comparison of the two known patients with Duane syndrome associated with deletion of 8q identifies a small region of overlap (SRO) of < 3 cM extending from D8S533 and D8S1767 in which a Duane syndrome locus is assigned. In addition YAC analysis in our patient showed that 8q rearrangement was rather complex since 8q deletion and insertion occurred in two distinct segments separated by a region which maintained its location on 8q.Keywords: chromosome 8; deletion; Duane syndrome; mapping; complex rearrangement IntroductionDuane syndrome is a primary form of strabismus consisting of an ocular motility defect with absent or severely limited abduction and variable limitation of adduction, associated with bilateral globe retraction and narrowing palpebral fissure. 1 This autosomal dominant (MIM 126800) disorder is responsible for approximately 1% of all strabismus cases. Duane syndrome has been clinically subclassified by Huber in three forms which cause deficiency of binocular sight due to altered ocular motility, eventually associated with nistagmus and other ocular anomalies. The pathogenesis of this syndrome is unknown but, in some patients at least, a muscular/neuronal origin has been proved. 187-193 © 1998 Stockton Press All rights reserved 1018-4813/98 $12.00 http://www.stockton-press.co.uk/ejhg Although Duane syndrome is considered a clinically distinct condition, genetic heterogeneity has been suspected. In fact a few atypical cases of Duane syndrome have been described in association with deafness, renal defects, muscular, and skeletal anomalies 4-7 and chromosome imbalances. [7][8][9][10] In particular a contiguous gene syndrome consisting of Duane syndrome, branchio-oto-renal syndrome (BOR), hydrocephalus and trapeze aplasia was found in a patient with 8q12.2-q21.2 deletion. 7 We report on an insertion deletion of chromosome 8q13-q21.2 in a patient presenting with Duane syndrome type I, severe mental retardation, and minor limbs abnormalities. Molecular studies were carried out in order to analyse and map this Duane syndrome containing region. Materials and Methods PatientA 7-year-old girl, the first child of unrelated parents, was referred for cytogenetic analysis on the basis of severe mental retardation and dysmorphisms. Family history was unremarkable. At birth her length was 48 cm and weight 3250 g. At 7 years of age, she was 119 cm in height (5th centile) and weighted 25 kg (65th centile). On clinical evaluation she presented with microcephaly, bil...

Narrowing the Duane syndrome critical region at chromosome 8q13 down to 40 kb

“…Fourteen STSs mapping within the Duane SRO at 8q13 6 and retrieved from CEPH/Généthon database 9 were tested by PCR on YAC clones to confirm integrity and on the PAC library for screening. Computer-aided search for sequences from genes and STS-ESTs mapped in the 8q13 region was performed using software available at the Whitehead Institute and Genome DataBase websites.…”

“…FISH and fibre-FISH analyses were performed according to Calabrese et al 6 and Fidlerova et al, 8 respectively. Biotinylated and FITC-labelled painting probes for chromosomes 6 and 8 (Cambio-Bouty, Italy), biotinylated 6q25-specific band probe (Li-Star FISH, Italy), YAC clones from contig WC8.8 (Géné-thon, France/Whitehead Institute, MIT, USA), PAC clones from RPCI-5 library (IGeR, Italy) were used.…”

“…4 Furthermore, chromosome anomalies have been observed in some Duane patients and an 8q12-13 contiguous gene syndrome including Duane syndrome has been proposed. 5 Recently, a comparison of boundaries in two patients with 8q13 deletions 5,6 allowed us to narrow down the Duane syndrome smallest region of overlap (SRO) to a < 3 cM interval between D8S533 and D8S1767. 6 In this study we report a Duane syndrome patient carrying a constitutional translocation involving region 8q13.…”

“…5 Recently, a comparison of boundaries in two patients with 8q13 deletions 5,6 allowed us to narrow down the Duane syndrome smallest region of overlap (SRO) to a < 3 cM interval between D8S533 and D8S1767. 6 In this study we report a Duane syndrome patient carrying a constitutional translocation involving region 8q13. Molecular analyses have allowed the refinement of the Duane locus, and the reassignment of the map position of the AMYB gene, proposed as a candidate gene due its expression in the hindbrain, neural retina and urogenital ridge.…”

Congenital innervation dysgenesis syndrome (CID)/congenital cranial dysinnervation disorders (CCDDs)

“…61 The DURS1 locus is assumed to reflect disruption of a gene for isolated DRS and is defined by cytogenetic abnormalities of 8q12.2-8q21.2. [62][63][64] The chromosome 8 break point was found to occur between exons 1 and 2 of a carboxypeptidase gene, CPA6 (CPAH), which is hypothesised to have a role in peptide processing in the brain. 64 …”