Fig. 5: Gonadal mosaicism and intrafamilial genetic heterogeneity are examples of pedigree-related challenges.

a Pedigree of family F4923 with 3 half siblings affected with Split hand/foot malformation syndrome. b Clinical image of the three affected siblings highlighting the hand malformations. c Screenshot of Bionano analysis output showing the identified heterozygous duplication on Chr10 previously associated with split hand/foot malformation syndrome. d Overview of structural variants identified in Chr10 by optical  genome mapping. e Table summarizing the identified disease-causing lesion in the family. f Pedigree of family F5162 with three siblings affected with variable degrees of intellectual disability, abnormal facial shape, and inability to completely open their jaws. Molecular analysis revealed that two siblings were homozygous for a LOF variant in THUMPD1 while the younger affected sibling had a de novo variant in HIST1H1E. g, h clinical images of affected individual IV:7 highlighting his inability to completely open his mouth. i, j Facial images of affected individual IV:8 demonstrating his incapacity to open his jaw.