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.
N1 - Publisher Copyright:
© 2023 American College of Medical Genetics and Genomics
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.
UR - http://www.scopus.com/inward/record.url?scp=85168369579&partnerID=8YFLogxK
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 -