Severe Form of Brachydactyly Type A1 in a Child with a c.298G &gt; A Mutation in IHH Gene

Salian, Smrithi; Shukla, Anju; Nishimura, Gen; Girisha, Katta M.

doi:10.1055/s-0037-1599201

Cited by 7 publications

(7 citation statements)

References 12 publications

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“…Reviewing published cases in addition to novel mutations identified by them, Byrnes et al [ 3 ] concluded that all BDA1 variants involving codons 95, 100, 128, 130, 131 and 154 are limited to a 59-amino acid region of the N-terminal active fragment (IHH-N) that spans codons 95–154 Soon after this review, Stattin et al [ 11 ] reported a Swedish family with a novel Arg158Cys mutation, showing that Byrnes et al’s [ 3 ] proposal is not always the case. Since then, some novel BDA1 associated variants have been reported in various populations [ 7 , 12 , 13 ]. However, to date, variants other than those involving codons 95, 100, 128, 130, 131, 154, and 158 have never been identified.…”

Section: Discussionmentioning

confidence: 99%

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Deletion of 2 amino acids in IHH in a Japanese family with brachydactyly type A1

Ozaki¹,

Okuda

Kobayashi

et al. 2021

BMC Med Genomics

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Background Brachydactyly type A1 (BDA1) is an autosomal dominant disorder characterized by uniform shortening of the middle phalanges in all digits. It is associated with variants in the Indian Hedgehog (IHH) gene, which plays a key role in endochondral ossification. To date, heterozygous pathogenic IHH variants involving several codons, which are restricted to a specific region of the N-terminal active fragment of IHH, have been reported. The purpose of this study was to identify the pathogenic variant in a Japanese family with BDA1 and to evaluate its pathogenesis with regard to previous reports. Methods The proband, a 9-year-old boy, his siblings, and his father had shortened digits and a short stature of variable severity. Based on physical examinations, radiographic findings and family history, they were diagnosed with BDA1. This family is the first case of an isolated malformation in Japan. Sanger sequencing of IHH was performed on these individuals and on the proband’s unaffected mother. The significance of the variants was assessed using three-dimensional analysis methods. Results Sanger sequencing showed a novel IHH heterozygous variant, NM_002181.4:c.544_549delTCAAAG(p.Ser182Lys183del) [NC_000002.12:g.219057461_219057466del].. These two residues are located outside the cluster region considered a hotspot of pathogenic variants. Three-dimensional modelling showed that S182 and K183 are located on the same surface as other residues associated with BDA1. Analysis of residue interactions across the interface between IHH and its interacting receptor protein revealed the presence of hydrogen bonds between them. Conclusions We report a novel variant, NM_002181.4:c.544_549delTCAAAG (p.Ser182Lys183del) [NC_000002.12:g.219057461_219057466del] in a Japanese family with BDA1. Indeed, neither variations in codons 182 or 183 nor with such two-amino-acid deletions in IHH have been reported previously. Although these two residues are located outside the cluster region considered a hotspot of pathogenic variants, we speculate that this variant causes BDA1 through impaired interactions between IHH and target receptor proteins in the same manner as other pathogenic variants located in the cluster region. This report expands the genetic spectrum of BDA1.

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Section: Discussionmentioning

confidence: 99%

“…This is interpreted as a common mechanism of the BDA1-causing variants [4]. Most IHH variants have been characterized as missense [1,3,[5][6][7][8][9][10][11][12], except for one insertion [13] and one deletion [14].…”

Section: Introductionmentioning

confidence: 99%

Deletion of 2 amino acids in IHH in a Japanese family with brachydactyly type A1

Ozaki¹,

Okuda

Kobayashi

et al. 2021

BMC Med Genomics

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“…It impairs chondrocyte maturation and proliferation, resulting in failure of osteoblast development in endochondral bones [7]. So far, about 14 IHH pathogenic variants have been reported to be associated with BD [11][12][13][14] (Fig. 4).…”

Section: Discussionmentioning

confidence: 99%

A novel variant of IHH in a Chinese family with brachydactyly type 1

et al. 2020

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Background: Brachydactyly type A1(BDA-1) is an autosomal dominant disorder which is caused by heterozygous pathogenic variants in a specific region of the N-terminal active fragment of Indian Hedgehog (IHH). The disorder is mainly characterized by shortening or missing of the middle phalanges. In this study, Our purpose is to identify the pathogenic variations associated with BDA-1 involved in a five-generation Chinese family. Methods: A BDA-1 family with 8 affected and 14 unaffected family members was recruited. Whole exome sequencing (WES) was performed to identify the pathogenic variant in the proband, and which was later confirmed and segregated by Sanger sequencing. The significance of variants were assessed using several molecular and bioinformatics analysis methods. Results: We uncovered a novel heterozygous missense variant c.299A > G (p.D100G) at the mutational hotspot of IHH gene following whole-exome sequencing of a Chinese family with BDA-1. The variant co-segregated with BDA-1 in the pedigree, showed 100% penetrance for phalange phenotype with variable expressivity. Conclusions: In conclusion, this study reports a five-generation Chinese family with BDA-1 due to a novel pathogenic variant (c.299A > G (p.D100G)) of IHH and expands the clinical and genetic spectrum of BDA-1.

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“…14 IHH pathogenic variants have been reported to be association with BD [11][12][13][14][ figure 4A], and the variants are restricted to the N-terminal active fragment, and exhibit a variable outcome [4]. Variants associated with brachydactyly type A1 are known to predominantly affect codon 95, 100, 131, and 154 [3,[15][16].…”

Section: Discussionmentioning

confidence: 99%

A novel pathogenic variant of IHH for Brachydactyly type A1

Yang¹,

Wang²,

Tian³

et al. 2019

Preprint

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Brachydactyly type A1 (BDA-1, MIM 112500) is a genetically heterogeneous autosomal-dominant disorder mainly characterized by shortening or missing of the middle phalanges. Brachydactyly type A1 (BDA-1) is caused by heterozygous pathogenic variants in a specific region of the N-terminal active fragment of Indian Hedgehog (IHH). In this study, we reported a Chinese family with 8 members affected with Brachydactyly type A1. After performing whole-exome sequencing in the proband, we identified a novel heterozygous missense variant c.299A>G (p.D100G) at the mutational hotspot of IHH gene. The variant co-segregated with BDA-1 in the pedigree, showed 100% penetrance for phalange phenotype with variable expressivity. This finding expanded the Brachydactyly type A1-related mutational spectrum of IHH gene.

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Severe Form of Brachydactyly Type A1 in a Child with a c.298G > A Mutation in IHH Gene

Abstract: Brachydactyly type A1 (BDA1) is characterized by short middle phalanges. We report the case of a child with a severe form of BDA1 with complete absence of the middle phalanges of all extremities. He had c.298G > A (p.D100N) mutation in gene.

Cited by 7 publications

References 12 publications

Deletion of 2 amino acids in IHH in a Japanese family with brachydactyly type A1

Deletion of 2 amino acids in IHH in a Japanese family with brachydactyly type A1

A novel variant of IHH in a Chinese family with brachydactyly type 1

A novel pathogenic variant of IHH for Brachydactyly type A1

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