Japanese founder duplications/triplications involving BHLHA9 are associated with split-hand/foot malformation with or without long bone deficiency and Gollop-Wolfgang complex

Eiko Nagata, Hiroki Kano, Fumiko Kato, Rie Yamaguchi, Shinichi Nakashima, Shinichiro Takayama, Rika Kosaki, Hidefumi Tonoki, Seiji Mizuno, Satoshi Watanabe, Koh Ichiro Yoshiura, Tomoki Kosho, Tomonobu Hasegawa, Mamori Kimizuka, Atsushi Suzuki, Kenji Shimizu, Hirofumi Ohashi, Nobuhiko Haga, Hironao Numabe, Emiko Horii & 11 others Toshiro Nagai, Hiroshi Yoshihashi, Gen Nishimura, Tatsushi Toda, Shuji Takada, Shigetoshi Yokoyama, Hiroshi Asahara, Shinichiro Sano, Maki Fukami, Shiro Ikegawa, Tsutomu Ogata

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

BACKGROUND: Limb malformations are rare disorders with high genetic heterogeneity. Although multiple genes/loci have been identified in limb malformations, underlying genetic factors still remain to be determined in most patients.

METHODS: This study consisted of 51 Japanese families with split-hand/foot malformation (SHFM), SHFM with long bone deficiency (SHFLD) usually affecting the tibia, or Gollop-Wolfgang complex (GWC) characterized by SHFM and femoral bifurcation. Genetic studies included genomewide array comparative genomic hybridization and exome sequencing, together with standard molecular analyses.

RESULTS: We identified duplications/triplications of a 210,050 bp segment containing BHLHA9 in 29 SHFM patients, 11 SHFLD patients, two GWC patients, and 22 clinically normal relatives from 27 of the 51 families examined, as well as in 2 of 1,000 Japanese controls. Families with SHFLD- and/or GWC-positive patients were more frequent in triplications than in duplications. The fusion point was identical in all the duplications/triplications and was associated with a 4 bp microhomology. There was no sequence homology around the two breakpoints, whereas rearrangement-associated motifs were abundant around one breakpoint. The rs3951819-D17S1174 haplotype patterns were variable on the duplicated/triplicated segments. No discernible genetic alteration specific to patients was detected within or around BHLHA9, in the known causative SHFM genes, or in the exome.

CONCLUSIONS: These results indicate that BHLHA9 overdosage constitutes the most frequent susceptibility factor, with a dosage effect, for a range of limb malformations at least in Japan. Notably, this is the first study revealing the underlying genetic factor for the development of GWC, and demonstrating the presence of triplications involving BHLHA9. It is inferred that a Japanese founder duplication was generated through a replication-based mechanism and underwent subsequent triplication and haplotype modification through recombination-based mechanisms, and that the duplications/triplications with various haplotypes were widely spread in Japan primarily via clinically normal carriers and identified via manifesting patients. Furthermore, genotype-phenotype analyses of patients reported in this study and the previous studies imply that clinical variability is ascribed to multiple factors including the size of duplications/triplications as a critical factor.

Original languageEnglish
Pages (from-to)125
Number of pages1
JournalOrphanet Journal of Rare Diseases
Volume9
DOIs
Publication statusPublished - 2014 Oct 21
Externally publishedYes

Fingerprint

Foot
Hand
Bone and Bones
Haplotypes
Exome
Extremities
Japan
Comparative Genomic Hybridization
Genetic Heterogeneity
Femur bifid with monodactylous ectrodactyly
Sequence Homology
Thigh
Tibia
Genetic Recombination
Genes
Genotype
Phenotype

ASJC Scopus subject areas

  • Medicine(all)
  • Genetics(clinical)
  • Pharmacology (medical)

Cite this

Japanese founder duplications/triplications involving BHLHA9 are associated with split-hand/foot malformation with or without long bone deficiency and Gollop-Wolfgang complex. / Nagata, Eiko; Kano, Hiroki; Kato, Fumiko; Yamaguchi, Rie; Nakashima, Shinichi; Takayama, Shinichiro; Kosaki, Rika; Tonoki, Hidefumi; Mizuno, Seiji; Watanabe, Satoshi; Yoshiura, Koh Ichiro; Kosho, Tomoki; Hasegawa, Tomonobu; Kimizuka, Mamori; Suzuki, Atsushi; Shimizu, Kenji; Ohashi, Hirofumi; Haga, Nobuhiko; Numabe, Hironao; Horii, Emiko; Nagai, Toshiro; Yoshihashi, Hiroshi; Nishimura, Gen; Toda, Tatsushi; Takada, Shuji; Yokoyama, Shigetoshi; Asahara, Hiroshi; Sano, Shinichiro; Fukami, Maki; Ikegawa, Shiro; Ogata, Tsutomu.

In: Orphanet Journal of Rare Diseases, Vol. 9, 21.10.2014, p. 125.

Research output: Contribution to journalArticle

Nagata, E, Kano, H, Kato, F, Yamaguchi, R, Nakashima, S, Takayama, S, Kosaki, R, Tonoki, H, Mizuno, S, Watanabe, S, Yoshiura, KI, Kosho, T, Hasegawa, T, Kimizuka, M, Suzuki, A, Shimizu, K, Ohashi, H, Haga, N, Numabe, H, Horii, E, Nagai, T, Yoshihashi, H, Nishimura, G, Toda, T, Takada, S, Yokoyama, S, Asahara, H, Sano, S, Fukami, M, Ikegawa, S & Ogata, T 2014, 'Japanese founder duplications/triplications involving BHLHA9 are associated with split-hand/foot malformation with or without long bone deficiency and Gollop-Wolfgang complex', Orphanet Journal of Rare Diseases, vol. 9, pp. 125. https://doi.org/10.1186/s13023-014-0125-5
Nagata, Eiko ; Kano, Hiroki ; Kato, Fumiko ; Yamaguchi, Rie ; Nakashima, Shinichi ; Takayama, Shinichiro ; Kosaki, Rika ; Tonoki, Hidefumi ; Mizuno, Seiji ; Watanabe, Satoshi ; Yoshiura, Koh Ichiro ; Kosho, Tomoki ; Hasegawa, Tomonobu ; Kimizuka, Mamori ; Suzuki, Atsushi ; Shimizu, Kenji ; Ohashi, Hirofumi ; Haga, Nobuhiko ; Numabe, Hironao ; Horii, Emiko ; Nagai, Toshiro ; Yoshihashi, Hiroshi ; Nishimura, Gen ; Toda, Tatsushi ; Takada, Shuji ; Yokoyama, Shigetoshi ; Asahara, Hiroshi ; Sano, Shinichiro ; Fukami, Maki ; Ikegawa, Shiro ; Ogata, Tsutomu. / Japanese founder duplications/triplications involving BHLHA9 are associated with split-hand/foot malformation with or without long bone deficiency and Gollop-Wolfgang complex. In: Orphanet Journal of Rare Diseases. 2014 ; Vol. 9. pp. 125.
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title = "Japanese founder duplications/triplications involving BHLHA9 are associated with split-hand/foot malformation with or without long bone deficiency and Gollop-Wolfgang complex",
abstract = "BACKGROUND: Limb malformations are rare disorders with high genetic heterogeneity. Although multiple genes/loci have been identified in limb malformations, underlying genetic factors still remain to be determined in most patients.METHODS: This study consisted of 51 Japanese families with split-hand/foot malformation (SHFM), SHFM with long bone deficiency (SHFLD) usually affecting the tibia, or Gollop-Wolfgang complex (GWC) characterized by SHFM and femoral bifurcation. Genetic studies included genomewide array comparative genomic hybridization and exome sequencing, together with standard molecular analyses.RESULTS: We identified duplications/triplications of a 210,050 bp segment containing BHLHA9 in 29 SHFM patients, 11 SHFLD patients, two GWC patients, and 22 clinically normal relatives from 27 of the 51 families examined, as well as in 2 of 1,000 Japanese controls. Families with SHFLD- and/or GWC-positive patients were more frequent in triplications than in duplications. The fusion point was identical in all the duplications/triplications and was associated with a 4 bp microhomology. There was no sequence homology around the two breakpoints, whereas rearrangement-associated motifs were abundant around one breakpoint. The rs3951819-D17S1174 haplotype patterns were variable on the duplicated/triplicated segments. No discernible genetic alteration specific to patients was detected within or around BHLHA9, in the known causative SHFM genes, or in the exome.CONCLUSIONS: These results indicate that BHLHA9 overdosage constitutes the most frequent susceptibility factor, with a dosage effect, for a range of limb malformations at least in Japan. Notably, this is the first study revealing the underlying genetic factor for the development of GWC, and demonstrating the presence of triplications involving BHLHA9. It is inferred that a Japanese founder duplication was generated through a replication-based mechanism and underwent subsequent triplication and haplotype modification through recombination-based mechanisms, and that the duplications/triplications with various haplotypes were widely spread in Japan primarily via clinically normal carriers and identified via manifesting patients. Furthermore, genotype-phenotype analyses of patients reported in this study and the previous studies imply that clinical variability is ascribed to multiple factors including the size of duplications/triplications as a critical factor.",
author = "Eiko Nagata and Hiroki Kano and Fumiko Kato and Rie Yamaguchi and Shinichi Nakashima and Shinichiro Takayama and Rika Kosaki and Hidefumi Tonoki and Seiji Mizuno and Satoshi Watanabe and Yoshiura, {Koh Ichiro} and Tomoki Kosho and Tomonobu Hasegawa and Mamori Kimizuka and Atsushi Suzuki and Kenji Shimizu and Hirofumi Ohashi and Nobuhiko Haga and Hironao Numabe and Emiko Horii and Toshiro Nagai and Hiroshi Yoshihashi and Gen Nishimura and Tatsushi Toda and Shuji Takada and Shigetoshi Yokoyama and Hiroshi Asahara and Shinichiro Sano and Maki Fukami and Shiro Ikegawa and Tsutomu Ogata",
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TY - JOUR

T1 - Japanese founder duplications/triplications involving BHLHA9 are associated with split-hand/foot malformation with or without long bone deficiency and Gollop-Wolfgang complex

AU - Nagata, Eiko

AU - Kano, Hiroki

AU - Kato, Fumiko

AU - Yamaguchi, Rie

AU - Nakashima, Shinichi

AU - Takayama, Shinichiro

AU - Kosaki, Rika

AU - Tonoki, Hidefumi

AU - Mizuno, Seiji

AU - Watanabe, Satoshi

AU - Yoshiura, Koh Ichiro

AU - Kosho, Tomoki

AU - Hasegawa, Tomonobu

AU - Kimizuka, Mamori

AU - Suzuki, Atsushi

AU - Shimizu, Kenji

AU - Ohashi, Hirofumi

AU - Haga, Nobuhiko

AU - Numabe, Hironao

AU - Horii, Emiko

AU - Nagai, Toshiro

AU - Yoshihashi, Hiroshi

AU - Nishimura, Gen

AU - Toda, Tatsushi

AU - Takada, Shuji

AU - Yokoyama, Shigetoshi

AU - Asahara, Hiroshi

AU - Sano, Shinichiro

AU - Fukami, Maki

AU - Ikegawa, Shiro

AU - Ogata, Tsutomu

PY - 2014/10/21

Y1 - 2014/10/21

N2 - BACKGROUND: Limb malformations are rare disorders with high genetic heterogeneity. Although multiple genes/loci have been identified in limb malformations, underlying genetic factors still remain to be determined in most patients.METHODS: This study consisted of 51 Japanese families with split-hand/foot malformation (SHFM), SHFM with long bone deficiency (SHFLD) usually affecting the tibia, or Gollop-Wolfgang complex (GWC) characterized by SHFM and femoral bifurcation. Genetic studies included genomewide array comparative genomic hybridization and exome sequencing, together with standard molecular analyses.RESULTS: We identified duplications/triplications of a 210,050 bp segment containing BHLHA9 in 29 SHFM patients, 11 SHFLD patients, two GWC patients, and 22 clinically normal relatives from 27 of the 51 families examined, as well as in 2 of 1,000 Japanese controls. Families with SHFLD- and/or GWC-positive patients were more frequent in triplications than in duplications. The fusion point was identical in all the duplications/triplications and was associated with a 4 bp microhomology. There was no sequence homology around the two breakpoints, whereas rearrangement-associated motifs were abundant around one breakpoint. The rs3951819-D17S1174 haplotype patterns were variable on the duplicated/triplicated segments. No discernible genetic alteration specific to patients was detected within or around BHLHA9, in the known causative SHFM genes, or in the exome.CONCLUSIONS: These results indicate that BHLHA9 overdosage constitutes the most frequent susceptibility factor, with a dosage effect, for a range of limb malformations at least in Japan. Notably, this is the first study revealing the underlying genetic factor for the development of GWC, and demonstrating the presence of triplications involving BHLHA9. It is inferred that a Japanese founder duplication was generated through a replication-based mechanism and underwent subsequent triplication and haplotype modification through recombination-based mechanisms, and that the duplications/triplications with various haplotypes were widely spread in Japan primarily via clinically normal carriers and identified via manifesting patients. Furthermore, genotype-phenotype analyses of patients reported in this study and the previous studies imply that clinical variability is ascribed to multiple factors including the size of duplications/triplications as a critical factor.

AB - BACKGROUND: Limb malformations are rare disorders with high genetic heterogeneity. Although multiple genes/loci have been identified in limb malformations, underlying genetic factors still remain to be determined in most patients.METHODS: This study consisted of 51 Japanese families with split-hand/foot malformation (SHFM), SHFM with long bone deficiency (SHFLD) usually affecting the tibia, or Gollop-Wolfgang complex (GWC) characterized by SHFM and femoral bifurcation. Genetic studies included genomewide array comparative genomic hybridization and exome sequencing, together with standard molecular analyses.RESULTS: We identified duplications/triplications of a 210,050 bp segment containing BHLHA9 in 29 SHFM patients, 11 SHFLD patients, two GWC patients, and 22 clinically normal relatives from 27 of the 51 families examined, as well as in 2 of 1,000 Japanese controls. Families with SHFLD- and/or GWC-positive patients were more frequent in triplications than in duplications. The fusion point was identical in all the duplications/triplications and was associated with a 4 bp microhomology. There was no sequence homology around the two breakpoints, whereas rearrangement-associated motifs were abundant around one breakpoint. The rs3951819-D17S1174 haplotype patterns were variable on the duplicated/triplicated segments. No discernible genetic alteration specific to patients was detected within or around BHLHA9, in the known causative SHFM genes, or in the exome.CONCLUSIONS: These results indicate that BHLHA9 overdosage constitutes the most frequent susceptibility factor, with a dosage effect, for a range of limb malformations at least in Japan. Notably, this is the first study revealing the underlying genetic factor for the development of GWC, and demonstrating the presence of triplications involving BHLHA9. It is inferred that a Japanese founder duplication was generated through a replication-based mechanism and underwent subsequent triplication and haplotype modification through recombination-based mechanisms, and that the duplications/triplications with various haplotypes were widely spread in Japan primarily via clinically normal carriers and identified via manifesting patients. Furthermore, genotype-phenotype analyses of patients reported in this study and the previous studies imply that clinical variability is ascribed to multiple factors including the size of duplications/triplications as a critical factor.

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