A heterozygous duplication variant of the HOXD13 gene caused synpolydactyly type 1 with variable expressivity in a Chinese family

Zaib, Tahir; Ji, Wei; Saleem, Komal; Nie, Guangchen; Li, Chao; Cao, Lin; Xu, Baijun; Dong, Kai; Yu, Hanfei; Hao, Xuguang; Xue, Yan; Si, Shuhan; Jia, Xueyuan; Wu, Jie; Zhang, Xuelong; Guan, Rongwei; Ji, Guohua; Bai, Jing; Chen, Feng; Liu, Yong; Sun, Wenjing; Fu, Songbin

doi:10.1186/s12881-019-0908-6

Cited by 10 publications

(7 citation statements)

References 33 publications

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“…Previously, Reddy et al, found the p.G91del variant in a large British family with lamellar cataract and demonstrated defective folding and reduced solubility of the mutant protein [ 38 ]. Since then, the p.G91del variant has been reported in 14 families of various ethnicity, mostly causing autosomal dominant congenital nuclear or lamellar cataract, except one with esotropia and nystagmus along with congenital cataract [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

The genetic landscape of crystallins in congenital cataract

Berry

Ionides

Pontikos

et al. 2020

Orphanet J Rare Dis

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Background The crystalline lens is mainly composed of a large family of soluble proteins called the crystallins, which are responsible for its development, growth, transparency and refractive index. Disease-causing sequence variants in the crystallins are responsible for nearly 50% of all non-syndromic inherited congenital cataracts, as well as causing cataract associated with other diseases, including myopathies. To date, more than 300 crystallin sequence variants causing cataract have been identified. Methods Here we aimed to identify the genetic basis of disease in five multi-generation British families and five sporadic cases with autosomal dominant congenital cataract using whole exome sequencing, with identified variants validated using Sanger sequencing. Following bioinformatics analysis, rare or novel variants with a moderate to damaging pathogenicity score, were filtered out and tested for segregation within the families. Results We have identified 10 different heterozygous crystallin variants. Five recurrent variants were found: family-A, with a missense variant (c.145C>T; p.R49C) in CRYAA associated with nuclear cataract; family-B, with a deletion in CRYBA1 (c.272delGAG; p.G91del) associated with nuclear cataract; and family-C, with a truncating variant in CRYGD (c.470G>A; W157*) causing a lamellar phenotype; individuals I and J had variants in CRYGC (c.13A>C; T5P) and in CRYGD (c.418C>T; R140*) causing unspecified congenital cataract and nuclear cataract, respectively. Five novel disease-causing variants were also identified: family D harboured a variant in CRYGC (c.179delG; R60Qfs*) responsible for a nuclear phenotype; family E, harboured a variant in CRYBB1 (c.656G>A; W219*) associated with lamellar cataract; individual F had a variant in CRYGD (c.392G>A; W131*) associated with nuclear cataract; and individuals G and H had variants in CRYAA (c.454delGCC; A152del) and in CRYBB1 (c.618C>A; Y206*) respectively, associated with unspecified congenital cataract. All novel variants were predicted to be pathogenic and to be moderately or highly damaging. Conclusions We report five novel variants and five known variants. Some are rare variants that have been reported previously in small ethnic groups but here we extend this to the wider population and record a broader phenotypic spectrum for these variants.

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Section: Discussionmentioning

confidence: 99%

The genetic landscape of crystallins in congenital cataract

Berry

Ionides

Pontikos

et al. 2020

Orphanet J Rare Dis

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“…In fact, both variants had been identified in Danish families by Kjaer et al (2005); the longer duplication explained the polysyndactyly phenotype in a family from Seeland first described in 1932 (Kjaer et al, 2002). Polyalanine expansions in HOXD13 have since been described in Turkish (Tuzel et al, 2007), Pakistani (Wajid et al, 2009), and Chinese (Dai et al, 2005; Gong et al, 2011; Zaib et al, 2019; Zu et al, 2021) kindreds with congenital limb malformations.…”

Section: Resultsmentioning

confidence: 99%

“…Homozygous and heterozygous nonsense variants affecting the DNA binding site in the homeodomain of HOXD13 lead to a variety of limb abnormalities and other skeletal defects with reduced penetrance (Jamsheer et al, 2012; Kurban et al, 2011; Low & Newbury‐Ecob, 2012). In addition, variants in the polyalanine tract domains of HOXD13 result in SPD phenotypes (Akarsu et al, 1996; Albrecht et al, 2004; Brison et al, 2012; Gong et al, 2011; Goodman et al, 1997; Kjaer et al, 2005, 2002; Tuzel et al, 2007; Zaib et al, 2019; Zhou et al, 2014). However, alterations outside of these domains can cause a wide spectrum of clinical features making the differential diagnosis complicated.…”

Section: Introductionmentioning

confidence: 99%

Long‐read whole genome sequencing reveals HOXD13 alterations in synpolydactyly

et al. 2021

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Synpolydactyly 1, also called syndactyly type II (SDTY2), is a genetic limb malformation characterized by polydactyly with syndactyly involving the webbing of the third and fourth fingers, and the fourth and fifth toes. It is caused by heterozygous alterations in HOXD13 with incomplete penetrance and phenotypic variability. In our study, a five‐generation family with an SPD phenotype was enrolled in our Rare Disease Genomics Protocol. A comprehensive examination of three generations using Illumina short‐read whole‐genome sequencing (WGS) did not identify any causative variants. Subsequent WGS using Pacific Biosciences (PacBio) long‐read HiFi Circular Consensus Sequencing (CCS) revealed a heterozygous 27‐bp duplication in the polyalanine tract of HOXD13. Sanger sequencing of all available family members confirmed that the variant segregates with affected individuals. Reanalysis of an unrelated family with a similar SPD phenotype uncovered a 21‐bp (7‐alanine) duplication in the same region of HOXD13. Although ExpansionHunter identified these events in most individuals in a retrospective analysis, low sequence coverage due to high GC content in the HOXD13 polyalanine tract makes detection of these events challenging. Our findings highlight the value of long‐read WGS in elucidating the molecular etiology of congenital limb malformation disorders.

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“…Studies of genotypic and phenotypic correlations suggested that the longer the polyalanine tract was, the more severe the phenotype was observed ( Goodman et al, 1997 ). Variations of c.183_206dup, c.186_212dup ( Gong et al, 2011 ), and c.893G>A ( Wang et al, 2012 ) in HOXD13 and their co-segregation in affected individuals have been reported by several groups ( Sun et al, 2021 ; Wajid et al, 2009 ; Zaib et al, 2019 ). The variant c.925A>T in HOXD13 causes atypical SPD by impairing the downstream transcription of EPHA7 ( Guo et al, 2021 ).…”

Section: Introductionmentioning

confidence: 98%

Clinical and genetic analysis in Chinese families with synpolydactyly, and cellular localization of HOXD13 with different length of polyalanine tract

Chen

Zhao²,

Xu³

et al. 2023

Front. Genet.

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Synpolydactyly (SPD) is caused by mutations in the transcription factor gene HOXD13. Such mutations include polyalanine expansion (PAE), but further study is required for the phenotypic spectrum characteristics of HOXD13 PAE. We investigated four unrelated Chinese families with significant limb malformations. Three PAEs were found in the HOXD13 polyalanine coding region: c.172_192dup (p.Ala58_Ala64dup) in Family 1, c.169_192dup (p.Ala57_Ala64dup) in Family 2, and c.183_210dup (p.Ala62_Ala70dup) in Family 3 and Family 4. Interestingly, we identified a new manifestation of preaxial polydactyly in both hands in a pediatric patient with an expansion of seven alanines, a phenotype not previously noted in SPD patients. Comparing with the wild-type cells and mutant cells with polyalanine contractions (PACs), the HOXD13 protein with a PAE of nine-alanine or more was difficult to enter the nucleus, and easy to form inclusion bodies in the cytoplasm, and with the increase of PAE, the more inclusion bodies were formed. This study not only expanded the phenotypic spectrum of SPD, but also enriched our understanding of its pathogenic mechanisms.

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A heterozygous duplication variant of the HOXD13 gene caused synpolydactyly type 1 with variable expressivity in a Chinese family

Cited by 10 publications

References 33 publications

The genetic landscape of crystallins in congenital cataract

The genetic landscape of crystallins in congenital cataract

Long‐read whole genome sequencing reveals HOXD13 alterations in synpolydactyly

Clinical and genetic analysis in Chinese families with synpolydactyly, and cellular localization of HOXD13 with different length of polyalanine tract

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