Yuan-Harel-Lupski Syndrome

A number sign (#) is used with this entry because of evidence that Yuan-Harel-Lupski syndrome (YUHAL) is caused by a contiguous gene duplication of chromosome 17p12-p11.2, including the PMP22 (601097) and RAI1 (607642) genes.

Description

Yuan-Harel-Lupski syndrome is a complex neurodevelopmental disorder characterized by global developmental delay and early-onset peripheral neuropathy. The disorder comprises features of both demyelinating Charcot-Marie-Tooth disease type 1A (CMT1A; 118220), which results from duplication of the PMP22 gene on 17p12, and Potocki-Lupski syndrome (PTLS; 610883), which results from duplication of a slightly proximal region on 17p11.2 that includes the RAI1 gene. These 2 loci are about 2.5 Mb apart. The resultant YUHAL phenotype may be more severe in comparison to the individual contributions of each gene, with particularly early onset of peripheral neuropathy and features of both central and peripheral nervous system involvement (summary by Yuan et al., 2015).

Clinical Features

Yuan et al. (2015) reported 23 unrelated patients with contiguous gene duplications encompassing the PMP22 and RAI1 genes. Some clinical information was available for 17 patients who ranged in age from 11 months to 13 years, although 1 individual was 33 years old. Ten patients had previously been reported (see, e.g., Doco-Fenzy et al., 2008; Shaw et al., 2004; Balarin et al., 1999; Vissers et al., 2007). Many features were not assessed or not reported in some individuals. Most patients had feeding difficulties, hypotonia, and failure to thrive in infancy, and all had global developmental delay with delayed walking, speech delay, and behavioral difficulties. Dysmorphic features, variably present in about half of patients, included triangular face, downslanting palpebral fissures, strabismus, broad nose, smooth or long philtrum, thin upper lip, and abnormal ears. In addition to hypotonia, 9 individuals presented with clinical neuropathy by age 10, 6 of whom were younger than age 5. The neuropathy was associated with weakness and atrophy of the distal extremities resulting in unsteady or wide-based gait, distal sensory impairment, and hypo- or areflexia at the ankles, consistent with Charcot-Marie-Tooth disease. Electrophysiologic studies, performed in only some patients, showed decreased nerve conduction velocities. Nerve biopsy was performed in 1 patient and showed loss of myelinated fibers and onion bulb formations. Additional common but variable features included chronic constipation, foot deformities, joint laxity, and congenital heart defects often involving the left ventricular outflow system. Three patients had structural renal abnormalities and 2 of 4 patients who underwent spinal imaging had syringomyelia.

Cytogenetics

In 23 unrelated patients with a complex phenotype including both global developmental delay and early-onset peripheral neuropathy, Yuan et al. (2015) identified 23 different nonrecurrent duplications of chromosome 17p12-p11.2. The duplications, which ranged in size from 3.2 to 19.8 Mb, were contiguous gene duplications with the smallest region of overlap encompassing both the PMP22 and RAI1 genes. Fourteen (60.87%) cases had apparently simple duplication rearrangements, whereas 9 (39.13%) had complex genomic rearrangements (CGRs) with higher-level structural complexities. Breakpoint junctions could be analyzed for 5 of the 14 simple duplications, and the sequences suggested fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR) or microhomology-mediated end-joining (MMEJ) as potential mutational mechanisms. Of the 9 CGRs, patterns included 'DEL-NML-DUP,' 'DUP-NML-DUP,' 'DUP-NML-INV/DUP,' and 'TRP-NML-DUP.' At least 1 patient had a highly complex rearrangement with multiple structural abnormalities consistent with chromothripsis/chromoanasynthesis. The breakpoint junctions of the nonrecurrent rearrangements identified in this study were enriched with repetitive DNA sequences, suggesting a predisposition of this chromosomal region to genomic instability. Array CGH performed on 14 trios showed that all the rearrangements occurred de novo.