Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion

Eva Klopocki, Silke Lohan, Sandra C. Doelken, Sigmar Stricker, Charlotte W. Ockeloen, Renata Soares Thiele de Aguiar, Karina Lezirovitz, Regina Celia Mingroni Netto, Aleksander Jamsheer, Hitesh Shah, Ingo Kurth, Rolf Habenicht, Matthew Warman, Koenraad Devriendt, Ulrike Kordaß, Maja Hempel, Anna Rajab, Outi Mäkitie, Mohammed Naveed, Uppala Radhakrishna & 3 others Stylianos E. Antonarakis, Denise Horn, Stefan Mundlos

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Background: Split-hand/foot malformation (SHFM)-also known as ectrodactyly-is a congenital disorder characterised by severe malformations of the distal limbs affecting the central rays of hands and/or feet. A distinct entity termed SHFLD presents with SHFM and long bone deficiency. Mouse models suggest that a defect of the central apical ectodermal ridge leads to the phenotype. Although six different loci/mutations (SHFM1-6) have been associated with SHFM, the underlying cause in a large number of cases is still unresolved. Methods: High resolution array comparative genomic hybridisation (CGH) was performed in patients with SHFLD to detect copy number changes. Candidate genes were further evaluated for expression and function during limb development by whole mount in situ hybridisation and morpholino knock-down experiments. Results: Array CGH showed microduplications on chromosome 17p13.3, a locus previously associated with SHFLD. Detailed analysis of 17 families revealed that this copy number variation serves as a susceptibility factor for a highly variable phenotype with reduced penetrance, particularly in females. Compared to other known causes for SHFLD 17p duplications appear to be the most frequent cause of SHFLD. A ~11.8 kb minimal critical region was identified encompassing a single gene, BHLHA9, a putative basic loop helix transcription factor. Whole mount in situ hybridisation showed expression restricted to the limb bud mesenchyme underlying the apical ectodermal ridge in mouse and zebrafish embryos. Knock down of bhlha9 in zebrafish resulted in shortening of the pectoral fins. Conclusions: Genomic duplications encompassing BHLHA9 are associated with SHFLD and non-Mendelian inheritance characterised by a high degree of nonpenetrance with sex bias. Knock-down of bhlha9 in zebrafish causes severe reduction defects of the pectoral fin, indicating a role for this gene in limb development.

Original languageEnglish
Pages (from-to)119-125
Number of pages7
JournalJournal of Medical Genetics
Volume49
Issue number2
DOIs
Publication statusPublished - 01-02-2012

Fingerprint

Ectromelia
Zebrafish
Tibia
Foot
Comparative Genomic Hybridization
Extremities
Hand
In Situ Hybridization
Genes
Phenotype
Limb Buds
Sexism
Morpholinos
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Penetrance
Mesoderm
Transcription Factors
Embryonic Structures
Chromosomes
Mutation

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Klopocki, E., Lohan, S., Doelken, S. C., Stricker, S., Ockeloen, C. W., de Aguiar, R. S. T., ... Mundlos, S. (2012). Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion. Journal of Medical Genetics, 49(2), 119-125. https://doi.org/10.1136/jmedgenet-2011-100409
Klopocki, Eva ; Lohan, Silke ; Doelken, Sandra C. ; Stricker, Sigmar ; Ockeloen, Charlotte W. ; de Aguiar, Renata Soares Thiele ; Lezirovitz, Karina ; Netto, Regina Celia Mingroni ; Jamsheer, Aleksander ; Shah, Hitesh ; Kurth, Ingo ; Habenicht, Rolf ; Warman, Matthew ; Devriendt, Koenraad ; Kordaß, Ulrike ; Hempel, Maja ; Rajab, Anna ; Mäkitie, Outi ; Naveed, Mohammed ; Radhakrishna, Uppala ; Antonarakis, Stylianos E. ; Horn, Denise ; Mundlos, Stefan. / Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion. In: Journal of Medical Genetics. 2012 ; Vol. 49, No. 2. pp. 119-125.
@article{d213f298e8bc4413a25b358f1fcb6701,
title = "Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion",
abstract = "Background: Split-hand/foot malformation (SHFM)-also known as ectrodactyly-is a congenital disorder characterised by severe malformations of the distal limbs affecting the central rays of hands and/or feet. A distinct entity termed SHFLD presents with SHFM and long bone deficiency. Mouse models suggest that a defect of the central apical ectodermal ridge leads to the phenotype. Although six different loci/mutations (SHFM1-6) have been associated with SHFM, the underlying cause in a large number of cases is still unresolved. Methods: High resolution array comparative genomic hybridisation (CGH) was performed in patients with SHFLD to detect copy number changes. Candidate genes were further evaluated for expression and function during limb development by whole mount in situ hybridisation and morpholino knock-down experiments. Results: Array CGH showed microduplications on chromosome 17p13.3, a locus previously associated with SHFLD. Detailed analysis of 17 families revealed that this copy number variation serves as a susceptibility factor for a highly variable phenotype with reduced penetrance, particularly in females. Compared to other known causes for SHFLD 17p duplications appear to be the most frequent cause of SHFLD. A ~11.8 kb minimal critical region was identified encompassing a single gene, BHLHA9, a putative basic loop helix transcription factor. Whole mount in situ hybridisation showed expression restricted to the limb bud mesenchyme underlying the apical ectodermal ridge in mouse and zebrafish embryos. Knock down of bhlha9 in zebrafish resulted in shortening of the pectoral fins. Conclusions: Genomic duplications encompassing BHLHA9 are associated with SHFLD and non-Mendelian inheritance characterised by a high degree of nonpenetrance with sex bias. Knock-down of bhlha9 in zebrafish causes severe reduction defects of the pectoral fin, indicating a role for this gene in limb development.",
author = "Eva Klopocki and Silke Lohan and Doelken, {Sandra C.} and Sigmar Stricker and Ockeloen, {Charlotte W.} and {de Aguiar}, {Renata Soares Thiele} and Karina Lezirovitz and Netto, {Regina Celia Mingroni} and Aleksander Jamsheer and Hitesh Shah and Ingo Kurth and Rolf Habenicht and Matthew Warman and Koenraad Devriendt and Ulrike Korda{\ss} and Maja Hempel and Anna Rajab and Outi M{\"a}kitie and Mohammed Naveed and Uppala Radhakrishna and Antonarakis, {Stylianos E.} and Denise Horn and Stefan Mundlos",
year = "2012",
month = "2",
day = "1",
doi = "10.1136/jmedgenet-2011-100409",
language = "English",
volume = "49",
pages = "119--125",
journal = "Journal of Medical Genetics",
issn = "0022-2593",
publisher = "BMJ Publishing Group",
number = "2",

}

Klopocki, E, Lohan, S, Doelken, SC, Stricker, S, Ockeloen, CW, de Aguiar, RST, Lezirovitz, K, Netto, RCM, Jamsheer, A, Shah, H, Kurth, I, Habenicht, R, Warman, M, Devriendt, K, Kordaß, U, Hempel, M, Rajab, A, Mäkitie, O, Naveed, M, Radhakrishna, U, Antonarakis, SE, Horn, D & Mundlos, S 2012, 'Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion', Journal of Medical Genetics, vol. 49, no. 2, pp. 119-125. https://doi.org/10.1136/jmedgenet-2011-100409

Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion. / Klopocki, Eva; Lohan, Silke; Doelken, Sandra C.; Stricker, Sigmar; Ockeloen, Charlotte W.; de Aguiar, Renata Soares Thiele; Lezirovitz, Karina; Netto, Regina Celia Mingroni; Jamsheer, Aleksander; Shah, Hitesh; Kurth, Ingo; Habenicht, Rolf; Warman, Matthew; Devriendt, Koenraad; Kordaß, Ulrike; Hempel, Maja; Rajab, Anna; Mäkitie, Outi; Naveed, Mohammed; Radhakrishna, Uppala; Antonarakis, Stylianos E.; Horn, Denise; Mundlos, Stefan.

In: Journal of Medical Genetics, Vol. 49, No. 2, 01.02.2012, p. 119-125.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion

AU - Klopocki, Eva

AU - Lohan, Silke

AU - Doelken, Sandra C.

AU - Stricker, Sigmar

AU - Ockeloen, Charlotte W.

AU - de Aguiar, Renata Soares Thiele

AU - Lezirovitz, Karina

AU - Netto, Regina Celia Mingroni

AU - Jamsheer, Aleksander

AU - Shah, Hitesh

AU - Kurth, Ingo

AU - Habenicht, Rolf

AU - Warman, Matthew

AU - Devriendt, Koenraad

AU - Kordaß, Ulrike

AU - Hempel, Maja

AU - Rajab, Anna

AU - Mäkitie, Outi

AU - Naveed, Mohammed

AU - Radhakrishna, Uppala

AU - Antonarakis, Stylianos E.

AU - Horn, Denise

AU - Mundlos, Stefan

PY - 2012/2/1

Y1 - 2012/2/1

N2 - Background: Split-hand/foot malformation (SHFM)-also known as ectrodactyly-is a congenital disorder characterised by severe malformations of the distal limbs affecting the central rays of hands and/or feet. A distinct entity termed SHFLD presents with SHFM and long bone deficiency. Mouse models suggest that a defect of the central apical ectodermal ridge leads to the phenotype. Although six different loci/mutations (SHFM1-6) have been associated with SHFM, the underlying cause in a large number of cases is still unresolved. Methods: High resolution array comparative genomic hybridisation (CGH) was performed in patients with SHFLD to detect copy number changes. Candidate genes were further evaluated for expression and function during limb development by whole mount in situ hybridisation and morpholino knock-down experiments. Results: Array CGH showed microduplications on chromosome 17p13.3, a locus previously associated with SHFLD. Detailed analysis of 17 families revealed that this copy number variation serves as a susceptibility factor for a highly variable phenotype with reduced penetrance, particularly in females. Compared to other known causes for SHFLD 17p duplications appear to be the most frequent cause of SHFLD. A ~11.8 kb minimal critical region was identified encompassing a single gene, BHLHA9, a putative basic loop helix transcription factor. Whole mount in situ hybridisation showed expression restricted to the limb bud mesenchyme underlying the apical ectodermal ridge in mouse and zebrafish embryos. Knock down of bhlha9 in zebrafish resulted in shortening of the pectoral fins. Conclusions: Genomic duplications encompassing BHLHA9 are associated with SHFLD and non-Mendelian inheritance characterised by a high degree of nonpenetrance with sex bias. Knock-down of bhlha9 in zebrafish causes severe reduction defects of the pectoral fin, indicating a role for this gene in limb development.

AB - Background: Split-hand/foot malformation (SHFM)-also known as ectrodactyly-is a congenital disorder characterised by severe malformations of the distal limbs affecting the central rays of hands and/or feet. A distinct entity termed SHFLD presents with SHFM and long bone deficiency. Mouse models suggest that a defect of the central apical ectodermal ridge leads to the phenotype. Although six different loci/mutations (SHFM1-6) have been associated with SHFM, the underlying cause in a large number of cases is still unresolved. Methods: High resolution array comparative genomic hybridisation (CGH) was performed in patients with SHFLD to detect copy number changes. Candidate genes were further evaluated for expression and function during limb development by whole mount in situ hybridisation and morpholino knock-down experiments. Results: Array CGH showed microduplications on chromosome 17p13.3, a locus previously associated with SHFLD. Detailed analysis of 17 families revealed that this copy number variation serves as a susceptibility factor for a highly variable phenotype with reduced penetrance, particularly in females. Compared to other known causes for SHFLD 17p duplications appear to be the most frequent cause of SHFLD. A ~11.8 kb minimal critical region was identified encompassing a single gene, BHLHA9, a putative basic loop helix transcription factor. Whole mount in situ hybridisation showed expression restricted to the limb bud mesenchyme underlying the apical ectodermal ridge in mouse and zebrafish embryos. Knock down of bhlha9 in zebrafish resulted in shortening of the pectoral fins. Conclusions: Genomic duplications encompassing BHLHA9 are associated with SHFLD and non-Mendelian inheritance characterised by a high degree of nonpenetrance with sex bias. Knock-down of bhlha9 in zebrafish causes severe reduction defects of the pectoral fin, indicating a role for this gene in limb development.

UR - http://www.scopus.com/inward/record.url?scp=84855988700&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84855988700&partnerID=8YFLogxK

U2 - 10.1136/jmedgenet-2011-100409

DO - 10.1136/jmedgenet-2011-100409

M3 - Article

VL - 49

SP - 119

EP - 125

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 2

ER -