Chromosome 22q11 deletion and pachygyria characterized by array‐based comparative genomic hybridization

With interest, wehave read the article byEhara et al. [2003], describing a patient with a 22q11 deletion and pachygyria and polymicrogyria. Chromosome 22q11 deletions are the most frequently occurring interstitial deletions found in men with an incidence of 1 in 4,000 live births [Burn and Goodship, 1996] and are associated with DiGeorge syndrome, velocardiofacial syndrome (VCFS), and conotruncal anomaly face syndrome [Devriendt et al., 1998]. These deletions have been reported in association with a wide variety of different birth defects and malformations occurring in various combinations and with a marked variety of clinical expression. Central nervous system (CNS) dysfunction, such as psychiatric illness, moderate cognitive impairment, and behavior problems, are considered to be part of the 22q11 deletion syndrome [Cohen et al., 1999; Scambler, 2000; McDermid and Morrow, 2002]. However, cortical anomalies have only rarely been reported in this syndrome (reviewed by [Ehara et al., 2003]). We report an 11-year-old girlwith severemental retardation (MR), a 22q11.2 deletion, pachygyria, and heterotopia. A full coverage chromosome 22 specific array-based comparative genomic hybridization (arrayCGH) was used to ascertain whether other gene copy number changes on chromosome 22q11 could be causative for the cortical dysplasia in this patient. The typical 3Mbdeletion, observed in themajority of 22q11 deletion patients, was detected without additional copy number aberrations to explain the severity of her phenotype. The girl was born at 333=7 weeks of gestation by normal vaginal delivery. Birth weight was 2,550 g (80th centile) and head circumference was 33.5 cm (98th centile). The unrelated parents had three healthy children, no miscarriages, and no history of mental retardation in their families. Developmental delay and feeding problems led to an evaluation by a pediatrician at 8 months of age. An enlarged adenoid, which caused an obstructive nasal stridor, a bifid uvula and a paraumbilical hernia were noted. Adenoidectomy was performed. Further laboratory analyses, including metabolic and lysosomal enzyme screening, showed no specific abnormalities. Cytogenetic studies showed a normal female karyotype (Gbanding at a 550 band level). Valproic acid was started at the age of 2 years because of marked epileptiform abnormalities in the right hemisphere and some diffuse bilateral epileptiform activity on electroencephalogram, although no motor seizures were noted. Computed tomography of the cerebrum at the age of 2 years revealed abnormal gyri. Cranialmagnetic resonance imaging (MRI) showed fronto-central and temporo-parietal pachygyria in the right hemisphere, bilateral subcortical heterotopia and enlarged Sylvian fissures (Fig. 1A,B) as described by Bingham et al. [1997, 1998]. Miller–Dieker lissencephalywas excluded byfluorescent in situhybridization (FISH) analysis using Miller–Dieker 17p13.3 region specific probes. The patient’s grossmotormilestones were delayed: she sat at 16months andwas not able to stand independently until 9 years. Examination at the age of 10 years showed a girl with severe MR. Expressive language skills were absent. Her length was 1.23 m (<0.6th centile) and her head circumference was 52 cm (30th centile). She had narrow palpebral fissures, a prominent chin, a small mouth, a bifid uvula, and several teeth were missing (Fig. 1C-D). Her hands were narrow with long slender fingers. She had narrow feet with flat arches and some equinus deformity (Fig. 1E-F). She had a disturbed ataxic gait pattern and some hirsutism of the lower limbs. At the age of 10 years, a 22q11.2 deletion was detected by FISH analysis using the TUPLE-1 probe, whereas the parents showed normal hybridization signals. The 22q11.2 deletion was further characterized using array-based comparative genomic hybridization (arrayCGH). A full coverage chromosome 22 array was constructed using degenerate oligonucleotide primingPCR products from 354 positionally selected chromosome 22 BAC clones (BACPAC Resources). Array fabrication, hybridization and analysis were performed as described previously [Veltman et al., 2003; Vissers et al., 2003]. In the proband, the 22q11.2 deletion was confirmed by arrayCGH and was molecularly characterized by 21 clones encompassing a 2.67 Mb genomic interval (Fig. 1G), according to the UCSC genome browser (July 2003 Freeze). The proximal breakpoint mapped between clone CTD-2536F14 and CTD-2280L11, whereas the distal breakpoint resided between clone RP11294A09 and CTD-2295P14. A recent haplotype analysis by Carlson et al. [1997] showed that>90% of patients with VCFS and a 22q11 deletion had a typically deleted region of 3 Mb, flanked by low copy repeat clusters (LCR) mediating nonhomologous recombination [Edelmann et al., 1999a,b; Shaikh et al., 1999, 2000]. The arrayCGH profile of this patient revealed that the deletion was similar to the typically deleted genomic interval and included the major genetic determinant of the 22q11 deletion syndrome, TBX1 [Yagi et al., 2003]. The breakpoints were within LCR regions, adjacent to the typically deleted region. These results do not provide indication for additional gene copy number aberrations on chromosome 22q11 in this patient. One might still hypothesize that pachygyria and heterotopia in the 22q11 deletion syndromemay result from dysregulation ofmodifying *Correspondence to: Bert B.A. de Vries, M.D., Ph.D., Department of Human Genetics, 417, University Medical Centre Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: B.deVries@antrg.umcn. nl