Frances R. Goodman, Chiara Bacchelli, Angela F. Brady, Louise A

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Novel HOXA13 Mutations and the Phenotypic Spectrum of Hand-Foot-Genital Syndrome Frances R. Goodman, Chiara Bacchelli, Angela F. Brady, Louise A. Brueton, Jean-Pierre Fryns, Douglas P. Mortlock, Jeffrey W. Innis, Lewis B. Holmes, Alan E. Donnenfeld, Murray Feingold, Frits A. Beemer, Raoul C.M. Hennekam, Peter J. Scambler The American Journal of Human Genetics Volume 67, Issue 1, Pages 197-202 (July 2000) DOI: 10.1086/302961 Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree drawings. A, Family 1; B, family 2; C, family 3; D, family 4; and E, family 5. Black shading of the left half of symbols indicates hand and foot abnormalities. Gray shading of the right half of symbols indicates genital abnormalities (hypospadias or other penile abnormality in males; uterine and/or vaginal abnormalities in females). An asterisk (*) above a symbol indicates that the individual had a urinary tract abnormality on diagnostic imaging. The American Journal of Human Genetics 2000 67, 197-202DOI: (10.1086/302961) Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 2 Limb abnormalities in II.2 from family 1 at age 8 years. Photographs of left hand (A), showing short, proximally placed thumb, ulnar deviation of the second finger, and clinodactyly of the fifth finger; and left foot (B), showing short, medially deviated hallux. Radiographs of both hands (C), showing short first metacarpals, small pointed first distal phalanges, hypoplastic second and fifth middle phalanges, proximal pseudoepiphyses of the second metacarpals and delayed ossification of the carpal centers; and both feet (D), showing short first metatarsals, small triangular first proximal and distal phalanges, absent ossification of the third to fifth middle phalanges, and hypoplasia/absence of the distal phalanges. The American Journal of Human Genetics 2000 67, 197-202DOI: (10.1086/302961) Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 3 Limb abnormalities in II.1 from family 5. Photographs at age 1 mo of left hand (A), showing extremely small thumb; and right foot (B), showing absence of hallux. Radiographs at age 5 years of both hands (C), showing extremely short first metacarpals, small pointed first distal phalanges, marked hypoplasia of all middle phalanges, especially the second and fifth, pseudoepiphyses of the third and fourth middle phalanges and the first and second metacarpals, and delayed ossification of the carpal centers; and both feet (D), showing absence of first digits apart from rudimentary bases of the first metatarsals, hypoplasia/absence of all middle phalanges, lack of epiphyses associated with the middle and distal phalanges, and abnormal tarsals with absent or fused cuneiforms. The American Journal of Human Genetics 2000 67, 197-202DOI: (10.1086/302961) Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 4 Mutations in HOXA13. A, Genomic structure of HOXA13, showing sites of the five mutations identified in this study. B, Wild-type HOXA13 protein. C–F, Predicted truncated mutant proteins in family 1 (C), lacking the last 253 amino acids; family 2 (D), lacking the last 193 amino acids; family 3 (E), lacking the last 24 amino acids; and family previously investigated by Mortlock and Innis (1997) (F), lacking the last 20 amino acids. G, Stable truncated mutant protein in the Hypodactyly mouse (Post et al. 2000), caused by a frameshift mutation in exon 1 of Hoxa13; the first 25 amino acids are followed by 275 amino acids with no wild-type counterpart and a premature stop codon. The American Journal of Human Genetics 2000 67, 197-202DOI: (10.1086/302961) Copyright © 2000 The American Society of Human Genetics Terms and Conditions