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

Genet Med. 2023 Nov;25(11):100928. doi: 10.1016/j.gim.2023.100928. Epub 2023 Jul 7.

Affiliations

¹ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Medizinische Genetik und Humangenetik, Berlin, Germany.
² Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Medizinische Genetik und Humangenetik, Berlin, Germany; Max Planck Institute for Molecular Genetics, RG Development & Disease, Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, Berlin, Germany.
³ Handsurgery Department, Children's Hospital Wilhelmstift, Hamburg, Germany.
⁴ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Medizinische Genetik und Humangenetik, Berlin, Germany; Labor Berlin Charité Vivantes GmbH, Department of Human Genetics, Berlin, Germany.
⁵ Max Planck Institute for Molecular Genetics, Human Molecular Genomics Group, Berlin, Germany; Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany.
⁶ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Medizinische Genetik und Humangenetik, Berlin, Germany; Max Planck Institute for Molecular Genetics, RG Development & Disease, Berlin, Germany.
⁷ Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland; Centers for Medical Genetics, GENESIS, Poznan, Poland.
⁸ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Medizinische Genetik und Humangenetik, Berlin, Germany; Max Planck Institute for Molecular Genetics, RG Development & Disease, Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Digital Clinician Scientist Program, Berlin, Germany. Electronic address: martin-atta.mensah@charite.de.

PMID: 37427568
DOI: 10.1016/j.gim.2023.100928

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.

Keywords: Alanine repeat expansion; Genotype-phenotype correlation; HOXD13; Synpolydactyly type 1.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Alanine / genetics
Genotype
Homeodomain Proteins* / genetics
Humans
Mutation
Pedigree
Phenotype
Syndactyly* / genetics
Transcription Factors / genetics

Substances

Homeodomain Proteins
Transcription Factors
Alanine
HOXD13 protein, human

Supplementary concepts

Syndactyly, type 2