Haplotype analyses of families with infantile cortical hyperostosis. (A) Family 1: Fine mapping of the locus for Caffey disease on chromosome 17q21. Standard techniques were used to establish the genetic locus of the disease in a large Canadian family with ADC (7, 8). Black symbols, affected individuals; white symbols with black dot in the center, obligate carriers; white symbols, unaffected individuals; gray symbols, deceased individuals. The unaffected individual II-9, who has unaffected children and grandchildren (data not shown), was only included to deduce the haplotypes of I-1 and I-2 (indicated by italics); for LOD score calculations, his phenotype was entered as unknown. Marker D17S1795 provided a LOD score of 6.78 (maximal theoretical LOD score, 7.12). Markers D17S1868 and D17S1877 (indicated in white on a black background) define the centromeric and telomeric boundary, respectively. The disease-associated haplotype is shown by black numbers on gray; markers consistent with a recombination are shown by white numbers on black. Uninformative data and haplotypes not associated with the disease are shown by black numbers on white. A C↠T mutation at nucleotide 3040 of COL1A1 (see Figure 3) was identified by direct nucleotide sequence analysis only in affected members and obligate carriers. (B) Haplotypes of portions of the family shown in A and PCR-based confirmation of the identified mutation (see Methods). (C) Haplotypes and PCR analysis for family 2, comprising 2 affected brothers, their affected mother, and their healthy father. (D) Haplotypes and PCR analysis for family 3, comprising identical twin sisters affected by Caffey disease and their healthy parents and brother (19).