Congenital Arthrogryposis: An Extension of the 15q11.2 BP1-BP2 Microdeletion Syndrome?

The proximal 15q11–q13 region contains 5 breakpoints (BP1–BP5). The BP1-BP2 region spans approximately 500？kb and contains four evolutionarily conserved genes. The genes in this region are known to play a role in central nervous system development and/or function. Microdeletions within the 15q11.2 BP1-BP2 region have been reported in patients with neurological dysfunction, developmental delays, behavioral problems, and dysmorphic features. We report two unrelated subjects with the 15q11.2 BP1-BP2 microdeletion and presenting with congenital arthrogryposis, a feature which has not been previously reported as part of this newly recognized microdeletion syndrome. While arthrogryposis seen in these two subjects may be coincidental, we propose that congenital arthrogryposis may result from neurological dysfunction and involvement of the microdeletion of the 15q11.2 BP1-BP2 region, further expanding the phenotype of this microdeletion syndrome. We encourage others to report patients with this chromosome microdeletion and neurological findings to further characterize the clinical phenotype. 1. Introduction The proximal 15q11–q13 region contains 5 breakpoints (BP1–BP5) located at low copy repeats implicated in causing chromosomal anomalies, primarily deletions, and duplications due to nonallelic homologous recombination [1, 2]. The most widely recognized deletion in this region is associated with two syndromes, Prader-Willi (PWS) and Angelman (AS), depending on the parent of origin and errors in genomic imprinting. The classical 15q11–q13 deletion seen in PWS or AS is of two types, a longer type I deletion involving BP1 and BP3 or the shorter type II deletion involving BP2 and BP3. Those with the longer type I deletion, in either PWS or AS, are reported with a more severe phenotype than those with the type II deletion [3–5]. The BP1-BP2 region spans approximately 500？kb and contains four evolutionarily conserved genes that are not imprinted: NIPA1, NIPA2, CYFIP1, and TUBGCP5 [6]. These genes are implicated in playing a role in central nervous system development and function; for example, mutations of NIPA1 are associated with spastic paraplegia [7, 8]. The related NIPA2 gene is widely expressed in the central nervous system and encodes for a magnesium transporter [9]. The CYFIP1 gene encodes a protein that interacts with FMRP, the protein product of the FMR1 gene responsible for fragile X syndrome [10]. This syndrome is the most common cause of familial intellectual disability and primarily affects males [11]. The fourth gene, TUBGCP5, is a member of the