Autistic features with speech delay in a girl with an ∼1.5‐Mb deletion in 6q16.1, including GPR63 and FUT9

To the Editor: Chromosomal deletions involving 6q16 are rare with less than 30 cases being described to date (1– 4). Phenotypic features in patients with 6q16 deletions include mental retardation, growth restriction, occasional microcephaly, hypotonia, thin upper lip, and ear anomalies. Several of these patients manifested also Prader–Willi syndrome-like phenotype as a result of haploinsufficiency of the SIM1 gene on 6q16.3 (2, 5, 6). A number of independent reports have linked autism (7–11), schizophrenia (12, 13), and bipolar disorder (14–17) to chromosome 6q14.3-q23.2, and glutamate receptor ionotropic kainate 2 (GRIK2) in 6q16.3, G-protein-coupled receptor (GPR6) in 6q21, and myristoylated alanine-rich protein kinase C substrate (MARCKS) in 6q22.1 have been suggested as candidate genes (7). GRIK2 has been linked to and associated with autism (9, 18–20) and schizophrenia (12, 13). We report a 10-year-old girl with mild mental retardation and autistic features in whomwe identified a de novo apparently balanced translocation t(6;14)(q16;q22) associated with an 1.5-Mb deletion on chromosome 6q16.1. She is the fifth child of healthy and non-consanguineous parents. The family history, pregnancy, and delivery were uneventful. The patient’s motordevelopmenthasbeendelayedslightly; shebegan to sit unaided at 7 months and walk independently at 18 months. The speech developed at age of 5 years. Currently, the patient shows mild degree of intellectual impairment, uses only simple words, and builds very simple sentences. Her behavioral abnormalities include hyperactivity, aggressiveness, episodes of inappropriate laughter,andmultiplemovementstereotypies, including nail biting and hair pulling. According to the International Classification of Diseases and Related Health Problems (ICD-10) criteria, she demonstrates the spectrumof autistic features: abnormal attention span and interpersonal reactions, deficit in verbal communication, failure to develop social relationships and emotions, and activities with lack of symbolic play. Clinical examination showed no dysmorphic features or congenital malformations. She has a relative macrocephaly with occipital-frontal circumference 55 cm (90th percentile). Her weight and height are normal (both on 50th percentile). The patient has had two episodes of seizures during fever. Brain magnetic resonance imaging was unremarkable, and electroencephalography revealed non-specific changes in temporal regions that are not associated with epileptic activity. G-banded chromosome analysis revealed a de novo apparently balanced translocation t(6;14) (q16;q22), and genome-wide oligonucleotide array comparative genomic hybridization using a 385K array HG18_WG_CGH_v1 (NimbleGen Systems, Madison, WI) identified an 1.5-Mb deletion in chromosome 6q16.1 (Fig. 1a–c). The deleted region includes the FUT9, GPR63, FHL5, KLHL32, C6orf66, and AK091365 genes and two predicted genes C6orf167 and KIAA0776. The other identified changes in the genome represent known copy number polymorphisms. The deletion was verified by fluorescence in situ hybridization analysis with bacterial artificial chromosome (BAC) clones (Fig. 1d,e). The chromosome 14 breakpoint was mapped in 14q23.1, between two adjacent BAC clones RP11-1077A2 and RP11-103A23, which contain only the OTX2 gene ( 150 kb from the breakpoint). Mutations in OTX2 have been reported in patients with severe ocular malformations (21); thus, it is unlikely that OTX2 contributes to our patient’s phenotype by a position effect. Likewise, we believe that the function of GRIK2, localized 4 Mb distal to the deletion, is unaffected. We propose that GPR63may be responsible for the autistic spectrum features present in our patient. GPR63 is a member of a large G-protein-coupled receptor (GPCR) family that contains seven transmembrane domains and transduces extracellular signals through heterotrimeric G proteins. Together with two others GPCRs, PSP24 and GPR45, GPR63