Haploinsufficiency of CMIP in a Girl With Autism Spectrum Disorder and Developmental Delay due to a De Novo Deletion on Chromosome 16q23.2 Nathalie Van der Aa, Geert Vandeweyer, Edwin Reyniers, Sandra Kenis, Lina Dom, Geert Mortier, Liesbeth Rooms, and R. Frank Kooy In a developmentally delayed girl with an autism spectrum disorder, Single nucleotide polymorphism (SNP) array analysis showed a de novo 280 kb deletion on chromosome 16q23.2 involving two genes, GAN and CMIP. Inactivating mutations in GAN cause the autosomal recessive disorder giant axonal neuropathy, not present in our patient. CMIP was recently implicated in the etiology of specific language impairment by genome-wide association analysis. It modulates phonological short-term memory and hence plays an important role in language acquisition. Overlaps of specific language impairment and autism have been debated in the literature regarding the phenotypical language profile as well as etiology. Our patient illustrates that haploinsufficiency of CMIP may contribute to autism spectrum disorders. Our finding further supports the existence of a genetic overlap in the etiology of specific language impairment and autism. Autism Res 2012, ••: ••–••. © 2012 International Society for Autism Research, Wiley Periodicals, Inc. Keywords: language delay; autism; ASD; CMIP; intellectual disability Introduction Autism or Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder defined by dysfunction in three core domains: a deficit in social interaction, a deficit in language and communication and the presence of repetitive or restricted behavior and interests [APA, 2000]. The involvement of each of these domains in the clinical picture is variable and partial forms also occur (hence the term spectrum). Language problems and intellectual dis- ability commonly co-occur in autism [Williams, Botting, & Boucher, 2008]. A substantial language delay, defined as a lag in the age of the first spoken word or phrase is seen in approximately half of children with autism. Twin studies as well as familial clustering have indicated a strong genetic component to the ASD phenotype but unraveling the genetic etiology of autism has turned out to be more complicated than anticipated [Abrahams & Geschwind, 2008; Stephan, 2008]. Only a fraction of the cases can be explained by monogenic inheritance, but genome-wide association studies and copy-number varia- tion (CNV) analysis led to the identification of several autism susceptibility genes and contributing copy number variants [Anney et al., 2010; Pinto et al., 2010]. However, each susceptibility locus seems to have a rather small effect and accounts for only a small fraction of cases [Geschwind, 2009]. Thus, the search for additional genetic causes of ASD remains a permanent challenge. We here present a child with ASD in whom we identi- fied a de novo deletion of CMIP, a gene previously impli- cated in specific language impairment (SLI). Clinical Report The patient is the first child of healthy non- consanguineous Caucasian parents with an unremark- able family history. She was born by cesarean section for breech position after an uneventful pregnancy at 37 weeks with a birth weight of 2,320 g (20th centile), length of 45 cm (15th–20th centile) and occipital-frontal circumference of 34 cm (75th centile). No neonatal prob- lems were reported. The baby fixed and followed from 6 weeks and smiled at 8 weeks. At 5 months of age she was diagnosed with gastroesophageal reflux and was also noted to be slightly hypotonic. Introduction of solid foods at that age was problematic. She was investigated at 17 months because of global developmental delay. She had no words and had not started babbling at that stage. Motor development was assessed using the Bayley Scales From the Department of Medical Genetics, University and University Hospital of Antwerp, Antwerp, Belgium (N.V.d.A., G.V., E.R., G.M., L.R., R.F.K.); Department of Neurology-Childneurology, University and University Hospital of Antwerp, Antwerp, Belgium (S.K.); Department of Pediatric Neurology, Paola Kinderziekenhuis, Berchem, Belgium (L.D.) Received October 5, 2011; accepted for publication May 15, 2012 Address for correspondence and reprints: Nathalie Van der Aa, University and University Hospital, Antwerp, Center for Medical Genetics, Prins Boudewijnlaan 43, 2650 Edegem, Belgium. E-mail: nathalie.van.der.aa@uza.be Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/aur.1240 © 2012 International Society for Autism Research, Wiley Periodicals, Inc. RESEARCH ARTICLE INSAR 1 Autism Research ••: ••–••, 2012