HOXD13-associated synpolydactyly: Extending and validating the genotypic and phenotypic spectrum with 38 new and 49 published families

Annika Gottschalk; Henrike L. Sczakiel; Wiebke Hülsemann; Sarina Schwartzmann; Angela T. Abad-Perez; Johannes Grünhagen; Claus Eric Ott; Malte Spielmann; Denise Horn; Stefan Mundlos; Aleksander Jamsheer; Martin A. Mensah

doi:10.1016/j.gim.2023.100928

HOXD13-associated synpolydactyly: Extending and validating the genotypic and phenotypic spectrum with 38 new and 49 published families

Annika Gottschalk, Henrike L. Sczakiel, Wiebke Hülsemann, Sarina Schwartzmann, Angela T. Abad-Perez, Johannes Grünhagen, Claus Eric Ott, Malte Spielmann, Denise Horn, Stefan Mundlos, Aleksander Jamsheer, Martin A. Mensah^*

^*Corresponding author for this work

Institute of Human Genetics

5 Citations (Scopus)

Abstract

Purpose: HOXD13 is an important regulator of limb development. Pathogenic variants in HOXD13 cause synpolydactyly type 1 (SPD1). How different types and positions of HOXD13 variants contribute to genotype-phenotype correlations, penetrance, and expressivity of SPD1 remains elusive. Here, we present a novel cohort and a literature review to elucidate HOXD13 phenotype-genotype correlations. Methods: Patients with limb anomalies suggestive of SPD1 were selected for analysis of HOXD13 by Sanger sequencing, repeat length analysis, and next-generation sequencing. Literature was reviewed for HOXD13 heterozygotes. Variants were annotated for phenotypic data. Severity was calculated, and cluster and decision-tree analyses were performed. Results: We identified 98 affected members of 38 families featuring 11 different (likely) causative variants and 4 variants of uncertain significance. The most frequent (25/38) were alanine repeat expansions. Phenotypes ranged from unaffected heterozygotes to severe osseous synpolydactyly, with intra- and inter-familial heterogeneity and asymmetry. A literature review provided 160 evaluable affected members of 49 families with SPD1. Computer-aided analysis only corroborated a positive correlation between alanine repeat length and phenotype severity. Conclusion: Our findings support that HOXD13-protein condensation in addition to haploinsufficiency is the molecular pathomechanism of SPD1. Our data may, also, facilitate the interpretation of synpolydactyly radiographs by future automated tools.

Original language	English
Article number	100928
Journal	Genetics in Medicine
Volume	25
Issue number	11
Pages (from-to)	100928
ISSN	1098-3600
DOIs	https://doi.org/10.1016/j.gim.2023.100928
Publication status	Published - 11.2023

Funding

Henrike L. Sczakiel is a participant in the BIH Charité Junior Clinician Scientist Program and Martin A. Mensah in the BIH Charité Digital Clinician Scientist Program founded by the late Prof. Duska Dragun and funded by the Charité — Universitätsmedizin Berlin and the Berlin Institute of Health. The authors would like to thank all families for their participation. The authors thank Valerie Johnston, Gabriele Hildebrand, and Steve Viergutz for technical support. Henrike L. Sczakiel is a participant in the BIH Charité Junior Clinician Scientist Program and Martin A. Mensah in the BIH Charité Digital Clinician Scientist Program founded by the late Prof. Duska Dragun and funded by the Charité — Universitätsmedizin Berlin and the Berlin Institute of Health. Conceptualization: A.G. H.L.S. D.H. S.M. M.A.M.; Data Curation: A.G. H.L.S. W.H. S.S. A.T.A.-P. J.G. C.-E.O. M.S. D.H. S.M. A.J. M.A.M.; Formal Analysis: A.G. H.L.S. M.A.M.; Investigation: A.G. H.L.S. M.A.M.; Software: A.G. M.A.M.; Writing-original draft: A.G. H.L.S. M.A.M.; Writing-review and editing: A.G. H.L.S. W.H. S.S. A.T.A.-P. J.G. C.-E.O. M.S. D.H. S.M. A.J. M.A.M. An ethics vote by the Charité Ethics Committee has been obtained (application number: EA2/087/15). All participants provided a written informed consent in accordance with the Declaration of Helsinki. Data were de-identified, pseudonymized, minimized, and cumulated where possible.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 10 Reduced Inequalities

Research Areas and Centers

Research Area: Medical Genetics

DFG Research Classification Scheme

2.22-03 Human Genetics

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Cite this

Gottschalk, A., Sczakiel, H. L., Hülsemann, W., Schwartzmann, S., Abad-Perez, A. T., Grünhagen, J., Ott, C. E., Spielmann, M., Horn, D., Mundlos, S., Jamsheer, A., & Mensah, M. A. (2023). HOXD13-associated synpolydactyly: Extending and validating the genotypic and phenotypic spectrum with 38 new and 49 published families. Genetics in Medicine, 25(11), 100928. Article 100928. https://doi.org/10.1016/j.gim.2023.100928

@article{79aa93b898524c66bf99bb142ce6454f,

title = "HOXD13-associated synpolydactyly: Extending and validating the genotypic and phenotypic spectrum with 38 new and 49 published families",

abstract = "Purpose: HOXD13 is an important regulator of limb development. Pathogenic variants in HOXD13 cause synpolydactyly type 1 (SPD1). How different types and positions of HOXD13 variants contribute to genotype-phenotype correlations, penetrance, and expressivity of SPD1 remains elusive. Here, we present a novel cohort and a literature review to elucidate HOXD13 phenotype-genotype correlations. Methods: Patients with limb anomalies suggestive of SPD1 were selected for analysis of HOXD13 by Sanger sequencing, repeat length analysis, and next-generation sequencing. Literature was reviewed for HOXD13 heterozygotes. Variants were annotated for phenotypic data. Severity was calculated, and cluster and decision-tree analyses were performed. Results: We identified 98 affected members of 38 families featuring 11 different (likely) causative variants and 4 variants of uncertain significance. The most frequent (25/38) were alanine repeat expansions. Phenotypes ranged from unaffected heterozygotes to severe osseous synpolydactyly, with intra- and inter-familial heterogeneity and asymmetry. A literature review provided 160 evaluable affected members of 49 families with SPD1. Computer-aided analysis only corroborated a positive correlation between alanine repeat length and phenotype severity. Conclusion: Our findings support that HOXD13-protein condensation in addition to haploinsufficiency is the molecular pathomechanism of SPD1. Our data may, also, facilitate the interpretation of synpolydactyly radiographs by future automated tools.",

author = "Annika Gottschalk and Sczakiel, \{Henrike L.\} and Wiebke H{\"u}lsemann and Sarina Schwartzmann and Abad-Perez, \{Angela T.\} and Johannes Gr{\"u}nhagen and Ott, \{Claus Eric\} and Malte Spielmann and Denise Horn and Stefan Mundlos and Aleksander Jamsheer and Mensah, \{Martin A.\}",

note = "Publisher Copyright: {\textcopyright} 2023 American College of Medical Genetics and Genomics",

year = "2023",

month = nov,

doi = "10.1016/j.gim.2023.100928",

language = "English",

volume = "25",

pages = "100928",

journal = "Genetics in Medicine",

issn = "1098-3600",

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Gottschalk, A, Sczakiel, HL, Hülsemann, W, Schwartzmann, S, Abad-Perez, AT, Grünhagen, J, Ott, CE, Spielmann, M, Horn, D, Mundlos, S, Jamsheer, A & Mensah, MA 2023, 'HOXD13-associated synpolydactyly: Extending and validating the genotypic and phenotypic spectrum with 38 new and 49 published families', Genetics in Medicine, vol. 25, no. 11, 100928, pp. 100928. https://doi.org/10.1016/j.gim.2023.100928

TY - JOUR

T1 - HOXD13-associated synpolydactyly

T2 - Extending and validating the genotypic and phenotypic spectrum with 38 new and 49 published families

AU - Gottschalk, Annika

AU - Sczakiel, Henrike L.

AU - Hülsemann, Wiebke

AU - Schwartzmann, Sarina

AU - Abad-Perez, Angela T.

AU - Grünhagen, Johannes

AU - Ott, Claus Eric

AU - Spielmann, Malte

AU - Horn, Denise

AU - Mundlos, Stefan

AU - Jamsheer, Aleksander

AU - Mensah, Martin A.

PY - 2023/11

Y1 - 2023/11

N2 - Purpose: HOXD13 is an important regulator of limb development. Pathogenic variants in HOXD13 cause synpolydactyly type 1 (SPD1). How different types and positions of HOXD13 variants contribute to genotype-phenotype correlations, penetrance, and expressivity of SPD1 remains elusive. Here, we present a novel cohort and a literature review to elucidate HOXD13 phenotype-genotype correlations. Methods: Patients with limb anomalies suggestive of SPD1 were selected for analysis of HOXD13 by Sanger sequencing, repeat length analysis, and next-generation sequencing. Literature was reviewed for HOXD13 heterozygotes. Variants were annotated for phenotypic data. Severity was calculated, and cluster and decision-tree analyses were performed. Results: We identified 98 affected members of 38 families featuring 11 different (likely) causative variants and 4 variants of uncertain significance. The most frequent (25/38) were alanine repeat expansions. Phenotypes ranged from unaffected heterozygotes to severe osseous synpolydactyly, with intra- and inter-familial heterogeneity and asymmetry. A literature review provided 160 evaluable affected members of 49 families with SPD1. Computer-aided analysis only corroborated a positive correlation between alanine repeat length and phenotype severity. Conclusion: Our findings support that HOXD13-protein condensation in addition to haploinsufficiency is the molecular pathomechanism of SPD1. Our data may, also, facilitate the interpretation of synpolydactyly radiographs by future automated tools.

AB - Purpose: HOXD13 is an important regulator of limb development. Pathogenic variants in HOXD13 cause synpolydactyly type 1 (SPD1). How different types and positions of HOXD13 variants contribute to genotype-phenotype correlations, penetrance, and expressivity of SPD1 remains elusive. Here, we present a novel cohort and a literature review to elucidate HOXD13 phenotype-genotype correlations. Methods: Patients with limb anomalies suggestive of SPD1 were selected for analysis of HOXD13 by Sanger sequencing, repeat length analysis, and next-generation sequencing. Literature was reviewed for HOXD13 heterozygotes. Variants were annotated for phenotypic data. Severity was calculated, and cluster and decision-tree analyses were performed. Results: We identified 98 affected members of 38 families featuring 11 different (likely) causative variants and 4 variants of uncertain significance. The most frequent (25/38) were alanine repeat expansions. Phenotypes ranged from unaffected heterozygotes to severe osseous synpolydactyly, with intra- and inter-familial heterogeneity and asymmetry. A literature review provided 160 evaluable affected members of 49 families with SPD1. Computer-aided analysis only corroborated a positive correlation between alanine repeat length and phenotype severity. Conclusion: Our findings support that HOXD13-protein condensation in addition to haploinsufficiency is the molecular pathomechanism of SPD1. Our data may, also, facilitate the interpretation of synpolydactyly radiographs by future automated tools.

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UR - https://www.mendeley.com/catalogue/dc5db757-9979-372d-b604-ff6f35eceed5/

U2 - 10.1016/j.gim.2023.100928

DO - 10.1016/j.gim.2023.100928

M3 - Journal articles

C2 - 37427568

AN - SCOPUS:85168369579

SN - 1098-3600

VL - 25

SP - 100928

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 11

M1 - 100928

ER -

HOXD13-associated synpolydactyly: Extending and validating the genotypic and phenotypic spectrum with 38 new and 49 published families

Abstract

Funding

UN SDGs

Research Areas and Centers

DFG Research Classification Scheme

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