The duplication 17p13.3 phenotype: analysis of 21 families delineates developmental, behavioral and brain abnormalities, and rare variant phenotypes

Abstract

Chromosome 17p13.3 is a gene rich region that when deleted is associated with the well-known Miller-Dieker syndrome. A recently described duplication syndrome involving this region has been associated with intellectual impairment, autism and occasional brain MRI abnormalities. We report 34 additional patients from 21 families to further delineate the clinical, neurological, behavioral, and brain imaging findings. We found a highly diverse phenotype with inter- and intrafamilial variability, especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and LIS1 genes. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis, and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications. We did not confirm the association of early overgrowth with involvement of YWHAE and CRK, or growth failure with duplications of LIS1. Older patients were often overweight. Three variant phenotypes included cleft lip/palate (CLP), split hand/foot with long bone deficiency (SHFLD), and a connective tissue phenotype resembling Marfan syndrome. The duplications in patients with clefts appear to disrupt ABR, while the SHFLD phenotype was associated with duplication of BHLHA9 as noted in two recent reports. The connective tissue phenotype did not have a convincing critical region. Our experience with this large cohort expands knowledge of this diverse duplication syndrome.

Keywords: 17p13.3; ABR; BHLHA9; LIS1; YWHAE; autism; cleft lip/palate; marfanoid habitus; microarray; split hand foot long bone deficiency.

Figure 1

A map of chromosome band 17p13.3 showing the genome location and gene content of duplications in all 21 families in our study as well as 13 additional patients from the literature was made using the Custom Tracks function in the UCSC browser (http://genome.ucsc.edu). The map shows Group 1 dups in red, Group 2 dups in purple and Group 3 dups in blue so that the differences in duplication size and position are obvious. The map also shows other reported dups in gray [Bi et al., 2009; Bruno et al., 2010; Roos et al., 2009; Shimojima et al., 2010].

Figure 2

Facial photos of four patients from Group 1. Note the hypotonic face in Patient 8a1 (D).

Figure 3

Facial photos of eight patients from Group 2. Note the round faces and facial hypotonia in younger Patients 9, 10 and 16 (A–F), and the long faces with prominent jaw and pointed chins in older Patients 11, 12, 13 and 15 (G–L).

Figure 4

Serial photos of Patient 14 from 2.5 to 7 years. Note increasing weight and facial lengthening with increasing age.

Figure 5

Facial photos of five patients from Group 3. Note an inconsistent phenotype with normal appearance of Patient 19.

Figure 6

Facial photos of three individuals with cleft lip and palate including one pre-surgical photo (C) and the remainder with repaired cleft lip (A, B and D–F). Also note the typical dup 17p13 adult face in Patient 5a2 (F).

Figure 7

Facial and limb photos of a girl with split hand/foot with long bone deficiency show blepharophimosis, full cheeks and Robin sequence (A). She also has tibial deficiency with intercalary polydactyly and syndactyly (B–D).

Figure 8

Facial and body photos of Patient 11 show dysmorphic facial features (A, C), and an unusual marfanoid habitus with scoliosis (D) and long limbs and fingers (B–E). He also has a dilated aortic root.

Figure 9

Brain imaging. T1–weighted midline sagittal brain magnetic resonance images are shown from individuals from Group 1 (A–H), Group 2 (I–M), and Group 3 (Q–T), as well as from three normal individuals (N–P). The solid white bars seen in multiple images show the level of the obex, which typically marks the level of the most inferior portion of the vermis as seen in the normal controls (N–P). The dotted white bar in M marks the lower limit of the vermis, which is difficult to see because of Chiari malformation in this patient. These images show a mildly small cerebellar vermis in two of eight patients in Group 1 (C and D), and in all five patients in Group 2 (I–M). The arrow in E points to a mildly prominent primary fissure, which suggests mild atrophy. The asterisk in D marks the smallest vermis, with normal vermian anatomy not well seen, probably because the image is just off midline. The arrow in image I points to mild protrusion or ectopia of the mesial parietal lobes into the tentorial notch between the corpus callosum and superior vermis. The vermis appears normal in all patients in Group 3 (Q–T). The images also show steeply angled foramen magnum (B, C, G, H, I, K, L) and flat inferior occiput (D, G, H, I, M) in most patients in Groups 1 and 2.

Figure 10

Map of chromosome 17p13.3 shows possible critical regions for cerebellar vermis hypoplasia in red and autism in blue. The smaller critical regions were determined assuming a single locus for each disorder, while the larger regions allow for limited causal heterogeneity by removing the patient with the smallest duplication.

Figure 11

Map of chromosome 17p13.3 shows possible critical regions for rare abnormalities including cleft lip and palate (CLP) in blue, split hand/foot with long bone deficiency (SHFLD) in purple, and marfanoid habitus in red. The rearrangements associated with CLP and SHFLD suggest a more complex mechanism than simple duplication, as explained in the text. All three dups associated with CLP have one breakpoint located within the ABR gene. All 4 dups associated with SHFLD shown here as well as 16/17 additional dups associated with SHFLD from another recent report [Klopocki et al., 2012] have one breakpoint located within or between the ABR and TUSC5 genes, suggesting disruption of regulatory elements.