2q31.1 microdeletion syndrome: redefining the associated clinical phenotype

Dimitrov, Boyan; Balikova, Irina; Ravel, Thomy de; Esch, Hilde Van; Smedt, Maryse De; Baten, E; Vermeesch, Joris Robert; Bradinova, Irena; Simeonov, E; Devriendt, Koen; Fryns, Jean‐Pierre; Debeer, Philippe

doi:10.1136/jmg.2010.079491

Cited by 29 publications

(45 citation statements)

References 50 publications

(53 reference statements)

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“…Similar to the individuals reported by Dimitrov et al [2011], no common breakpoints were identified in our subjects, and no mechanism of rearrangement could be delineated.…”

Section: Molecular Analysissupporting

confidence: 63%

“…Several recent studies have proposed genotype-phenotype correlations for specific features associated with deletions at 2q31.1, including limb abnormalities [Mitter et al, 2010;Dimitrov et al, 2011]. Mitter et al [2010] characterized 8 individuals with interstitial deletions at 2q31.1.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Dimitrov et al [2011] characterized 5 individuals with interstitial deletions at 2q31.1 using a BAC microarray. Two subjects with mild limb abnormalities had deletions that encompassed the HOXD cluster and Severe bruxism Teeth missing, hearing loss, G-tube AFOs = Ankle-foot orthotics; dn = de novo; GD = growth delay; GI = gastrointestinal; ID = intellectual disability; mat.…”

Section: Discussionmentioning

confidence: 99%

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Refinement of the Region for Split Hand/Foot Malformation 5 on 2q31.1

et al. 2010

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Background: Deletions that encompass 2q31.1 have been proposed as a microdeletion syndrome with common clinical features, including intellectual disability/developmental delay, microcephaly, cleft palate, growth delay, and hand/foot anomalies. In addition, several genes within this region have been proposed as candidates for split hand-foot malformation 5 (SHFM5). Methods: To delineate the genotype-phenotype correlation between deletions of this region, we identified 14 individuals with deletions at 2q31.1 detected by microarray analysis for physical and developmental disabilities. Results: All subjects for whom detailed clinical records were available had neurological deficits of varying degree. Seven subjects with deletions encompassing the HOXD cluster had hand/foot anomalies of varying severity, including syndactyly, brachydactyly, and ectrodactyly. Of 7 subjects with deletions proximal to the HOXD cluster, 5 of which encompassed DLX1/DLX2, none had clinically significant hand/foot anomalies. In contrast to previous reports, the individuals in our study did not display a characteristic gestalt of dysmorphic facial features. Conclusion: The absence of hand/foot anomalies in any of the individuals with deletions of DLX1/DLX2 but not the HOXD cluster supports the hypothesis that haploinsufficiency of the HOXD cluster, rather than DLX1/DLX2, accounts for the skeletal abnormalities in subjects with 2q31.1 microdeletions.

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“…Similar to the individuals reported by Dimitrov et al [2011], no common breakpoints were identified in our subjects, and no mechanism of rearrangement could be delineated.…”

Section: Molecular Analysissupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Refinement of the Region for Split Hand/Foot Malformation 5 on 2q31.1

et al. 2010

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“…With the advent of array CGH, a number of additional deletions involving 2q31.1 have been identified and characterized, and attempts have been made to localize the regions responsible for different phenotypic features, including limb anomalies [Pescucci et al, 2007;Svensson et al, 2007;Davidsson et al, 2008;Tsai et al, 2009;Mitter et al, 2010;Dmitrov et al, 2011;Theisen et al, 2011]. Although it has also been hypothesized that deletion of the DLX1 and DLX2 genes, which reside centromeric to EVX2 and the HOXD cluster, may cause SHFM and other limb anomalies, this was not supported in two recent reports, and it appears that deletions excluding the HOXD cluster and its regulatory regions are not sufficient to cause limb anomalies [Dimitrov et al, 2011;Theisen et al, 2011].…”

Section: Balanced/unbalanced Chromosome Rearrangementsmentioning

confidence: 71%

“…This locus was identified from reports of cytogenetically visible deletions involving 2q31 in patients with syndromal SHFM. Variable limb anomalies, including SHFM, have been described in association with a number of other findings, such as growth delay, developmental disability, microcephaly, cleft palate, craniofacial dysmorphism, seizures, and anomalies of the brain, eyes, heart, and genitalia [Benson et al, 1986;Ramer et al, 1990;Boles et al, 1995;Nixon et al, 1997;Del Campo et al, 1999;Goodman et al, 2002;Pescucci et al, 2007;Svensson et al, 2007;Davidsson et al, 2008;Tsai et al, 2009;Mitter et al, 2010;Dimitrov et al, 2011;Theisen et al, 2011]. The deletions associated with SHFM have varied in size, and most have been sporadic, but some familial cases have been described [Ramer et al, 1990;Del Campo et al, 1999].…”

Section: Balanced/unbalanced Chromosome Rearrangementsmentioning

confidence: 99%

Clinical, genetic, and molecular aspects of split‐hand/foot malformation: An update

Gurrieri

Everman

2013

American J of Med Genetics Pt A

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We here provide an update on the clinical, genetic, and molecular aspects of split-hand/foot malformation (SHFM). This rare condition, affecting 1 in 8,500-25,000 newborns, is extremely complex because of its variability in clinical presentation, irregularities in its inheritance pattern, and the heterogeneity of molecular genetic alterations that can be found in affected individuals. Both syndromal and nonsyndromal forms are reviewed and the major molecular genetic alterations thus far reported in association with SHFM are discussed. This updated overview should be helpful for clinicians in their efforts to make an appropriate clinical and genetic diagnosis, provide an accurate recurrence risk assessment, and formulate a management plan.

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2q24 deletions: Further characterization of clinical findings and their relation to the SCN cluster

Nimmakayalu

Noble

Horton

et al. 2012

American J of Med Genetics Pt A

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As the resolution of molecular cytogenetic methods continues to improve, it has become increasingly possible to refine genotype-phenotype correlations based upon gene involvement. We report three new patients with nonrecurrent deletions involving subbands of 2q24. These patients were referred for evaluation of developmental delay, but were found to have unique, nonoverlapping clinical features. Patient 1 presented with infantile seizures, microcephaly, and brain anomalies, along with facial dysmorphism, growth retardation, neuromuscular scoliosis, and later with developmental regression. Array comparative genomic hybridization (aCGH) detected an 8 Mb interstitial deletion encompassing the neuronal sodium channel (SCN) gene cluster. Patient 2 presented with growth retardation, congenital heart defect, and hypotonia. Patient 3 presented with developmental delay and behavioral problems. Patients 2 and 3 had no history of seizures, microcephaly, or brain anomalies and were found to have deletions of 2q24, ∼8 Mb and <500 kb respectively, centromeric to and outside the SCN cluster. It has been demonstrated that mutations and copy number variants (CNVs) affecting the SCN gene cluster result in severe, early-onset seizures. It is however, less clear whether haploinsufficiency of regions outside the SCN cluster may result in phenotypically recognizable and clinically significant features. We discuss additional dosage sensitive genes that may exist outside the SCN cluster. Our and published data indicate that 2q24 deletions not involving the SCN cluster are associated with fewer neurobehavioral problems, but may predispose to congenital malformations.

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2q31.1 microdeletion syndrome: redefining the associated clinical phenotype

Cited by 29 publications

References 50 publications

Refinement of the Region for Split Hand/Foot Malformation 5 on 2q31.1

Refinement of the Region for Split Hand/Foot Malformation 5 on 2q31.1

Clinical, genetic, and molecular aspects of split‐hand/foot malformation: An update

2q24 deletions: Further characterization of clinical findings and their relation to the SCN cluster

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