Chromosome 17p13.3, Telomeric, Duplication Syndrome

A number sign (#) is used with this entry because of evidence that split-hand/foot malformation with long bone deficiency-3 (SHFLD3) is associated with a duplication involving one or more genes on chromosome 17p13.3. The duplication is less than 50% penetrant and shows markedly variable expressivity, including intraindividual variability.

For a general phenotypic description and discussion of genetic heterogeneity of split-hand/foot malformation with long bone deficiency, see SHFLD1 (119100).

Clinical Features

Richieri-Costa et al. (1987) reported a Brazilian family in which 8 members were affected with various limb abnormalities, including 2 sisters, offspring of consanguineous parents, who had different limb anomalies: the tibial aplasia-ectrodactyly syndrome was present in one and unilateral bifid femur with monodactylous ectrodactyly (see Gollop-Wolfgang complex, 228250) in the other.

Lezirovitz et al. (2008) restudied the large Brazilian family reported by Richieri-Costa et al. (1987), in which there were now 9 individuals affected by split-hand/foot malformation (SHFM) with long bone deficiency; 4 had SHFM without any tibial defects, 3 had both conditions, and 2 had only unilateral tibial hemimelia. Lezirovitz et al. (2008) noted that variable expression, incomplete penetrance, and the phenomenon of anticipation were observed in this 4-generation family.

Mapping

In a large Brazilian family with SHFLD3, previously reported by Richieri-Costa et al. (1987), Lezirovitz et al. (2008) performed linkage analysis and obtained a maximum 2-point lod score of 3.62 and a maximum multipoint lod score of 5.03 on chromosome 17p13.3-p13.1, at or near marker D17S1533. Lezirovitz et al. (2008) noted that their SHFLD locus was fully enclosed in the MSSD-type IX syndactyly locus mapped by Malik et al. (2005) (see 609432), and stated that the manifestations of both syndromes were so variable that the hypothesis that both forms were allelic could not be ruled out.

The smallest region of duplication overlap among 3 unrelated families with SHFLD reported by Armour et al. (2011) was a 173-kb region on chromosome 17p13.3 defined by genomic coordinates 956,201-1,128,916 (NCBI36). This region is within the putative region identified by Lezirovitz et al. (2008) and contains BHLHA9 (615416) and 3 of 24 coding exons of ABR (600365), as well as other putative transcripts. The candidate region does not include the YWHAE gene (605066) and is telomeric to another duplication of 17p13.3 described by Bruno et al. (2010) (see 613215).

Molecular Genetics

On the basis of segregation analysis and multipoint lod scores in a 4-generation Brazilian family with SHFLD3, Lezirovitz et al. (2008) defined a 3-cM candidate region between markers D17S1529 and D17S831, encompassing 18 known genes. Sequencing of candidate gene CRK (164762) did not reveal any pathogenic mutations.

Armour et al. (2011) reported 3 unrelated kindreds with SHFLD associated with distinct but overlapping duplications of chromosome 17p13.3. Inheritance was consistent with an autosomal dominant pattern with incomplete penetrance and variable expressivity. One family was a 3-generation Mennonite family with 5 affected individuals. Three had anomalies limited to the hands and 2 also had tibial hypoplasia or aplasia. All affected individuals and obligate carriers had a 254-kb duplication at 17p13.3. Twelve carriers of the duplication were unaffected, which Armour et al. (2011) attributed to incomplete penetrance. In the second family, the proband had multiple congenital limb anomalies. The right hand had 6 metacarpals with a thumb, 3 additional digits, and a deep central cleft between digits 2 and 3. The left hand contained 5 metacarpals, the third being bifid, but was otherwise similar to the right. Radiographs of the lower limbs revealed aplasia of the tibia. The right foot had only 4 metatarsals and 4 toes with a central cleft, and the left foot had 3 metatarsals with 2 toes and a central cleft. The proband and his unaffected mother both had a 527-kb duplication at 17p13.3. Three affected individuals from a third family had a 430-kb copy gain at 17p13.3. All had SHFLD, with variable upper limb and foot involvement and tibial a/hypoplasia requiring amputations and prostheses. It could not be conclusively determined whether the copy gain was a duplication or a triplication. None of the patients had neurodevelopmental problems.

In a 3-generation family with SHFM without tibial defects, Klopocki et al. (2012) identified a 180-kb duplication on chromosome 17p13.3. Analysis of a 4-generation Brazilian family with SHFLD, originally reported by Richieri-Costa et al. (1987) and mapped to 17p13.3-p13.1 by Lezirovitz et al. (2008), revealed a 110-kb microduplication in the same region. Screening of a cohort of another 54 families with nonsyndromic SHFM, including 11 cases with long bone deficiency (SHFLD), revealed 17p13.3 duplications in 15 more families, for a total of 17 (30%) of the 56 families overall, 12 with tibial aplasia and/or hypoplasia and 5 without. The duplication breakpoints were nonrecurrent and duplication sizes ranged from 69 kb to 594 kb, with an approximately 11.8-kb overlapping region. Combining these data with the overlapping 17p13.3 duplications detected by Armour et al. (2011) in 3 families with SHFLD localized the critical region between positions 1,117,153 and 1,128,916, encompassing a single gene, BHLHA9 (615416), a putative basic helix-loop-helix transcription factor. Klopocki et al. (2012) observed high phenotypic variability, with ectrodactyly of one or more extremities as the common clinical feature; tibial involvement was present in approximately 60% of affected individuals. In addition, there was a high degree of nonpenetrance, with duplications detected in 82 individuals, of whom 42 were affected and 40 were unaffected carriers. A clear sex bias was also observed, with more males (30 of 42) being affected than females (12 of 42). Klopocki et al. (2012) suggested that the duplication on 17p could be seen as a susceptibility factor for SHFLD which is necessary but not sufficient for development of the malformation. Noting that 17p33.3 duplications have been described in patients with mental retardation and autistic manifestations (see 613215), Klopocki et al. (2012) stated that evaluation of the patients with duplications from this cohort revealed no autistic features or developmental delay. In the remainder of the initial 56-family SHFM cohort that underwent screening, 10q24 duplications (SHFM3; 246560) were detected in 11 (20%) of the families and TP63 (603273) mutations (SHFM4; 605289) in 5 (9%).