Our series consisted of 29 patients, 17 males and 12 females, presenting with idiopathic ASD syndrome. The mean percentage of clones analysed for the whole series was 93%.
Thirty three chromosome gains or losses were detected in 22 patients. The size of the aneusomic segment varied from 200 kb (1 clone) to 16 Mb (19 clones).
To distinguish clinically relevant anomalies from normal chromosomal variants, we first took advantage of previously published studies looking for clones with copy number variability in normal people or otherwise suspected polymorphism.44,45,46
Twenty three variants had previously been described as normal variants in the general population and were therefore not further analysed (table 1). The 10 remaining variants were considered to be possibly pathogenic and were further investigated (table 2). Among these, seven were deletions and three were duplications. All deletions or duplications found are in distinct non‐overlapping regions. Figure 1 shows the array‐CGH profiles of these cases.
Table 1Details of the polymorphisms found in the cohort of our study
Table 2Patients with possibly pathogenic chromosomal anomalies
Figure 1Array‐based comparative genomic hybridisation ratio profiles showing chromosomal imbalances. For each graph, the x axis marks the distance from the telomere of the short arm (Mb) and the y axis marks the hybridisation ratio represented (more ...)
Confirmation of chromosomal anomalies by independent techniques
The 10 possibly pathogenic imbalances were then validated by at least one independent method: FISH or genotyping analysis of samples from the proband and both parents using either previously characterised microsatellites or new microsatellites identified from genomic sequence data in the critical regions. In one case (Xq25 duplication, patient 12), microarray analysis at tiling path resolution was carried out to confirm and refine the abnormal finding (data not shown). The deletion of case 5 was retrospectively visible on standard karyotype and was not further studied by FISH. In all cases, these analyses confirmed the chromosomal anomalies identified by array‐CGH.
To further show the clinical relevance of these chromosomal aberrations, clinically normal parents of nine patients were tested by FISH or genotyping to discriminate between de novo and inherited anomalies. The causal relationship remains uncertain for case 14 because the de novo occurrence could not be tested as parental blood samples were not available. Seven rearrangements occurred de novo; the two remaining cases (case 12 and 23) were shown to be inherited from a normal parent. The first is a Xq25 microduplication in a boy (case 12), inherited from his healthy mother who presented an X inactivation bias. The unaffected brother does not carry this microduplication. The second, case 23, is a 5p15.2 microdeletion, ranging from 200 kb to 1.3 Mb, inherited from the healthy mother and is hence likely to be non‐pathogenic.
Genotyping studies showed that 55.5% of the anomalies are of maternal origin and 45.5% paternal (table 2).
Table 3 summarises the clinical features of the patients (fig 2) with microdeletion or microduplication. These patients are briefly described below.
Table 3Clinical features observed in patients with clinically relevant chromosomal rearrangements
Figure 2Facial appearance of patients with chromosomal imbalance detected by array‐based comparative genomic hybridisation. (Photographs are reproduced with their parents' consent.)
Case 1 (46,XY,del(4)(q21.1q21.22)(4.8 Mb)) is a 20‐year‐old man, born at term with normal neonatal measurements and Apgar score. Pregnancy was marked by a toxoplasmic seroconversion between months 5 and 8 of gestation. He presented with delayed motor milestones, congenital malformations (Meckel diverticulum, ectopic testes, hypospadias, lumbar scoliosis and abnormal tooth position) and dysmorphic facial features (convergent strabismus, short philtrum and retrognatism). He developed postnatal short stature (−4 SD). He fulfils the DSM IV criteria for autism. Cerebral computed tomography scan showed periventricular calcifications. At age 14, cerebral magnetic resonance imaging (MRI) showed cerebellar atrophy.
Case 5 (46,XY,del(4)(q21.23q24)(16.5 Mb)) is a 12‐year‐old boy born at term with normal neonatal measurements. He presented with axial hypotonia, arthrogryposis, ectopic microtestes, congenital hip dislocation and large atrium septum defect. Motor development was delayed. He developed scoliosis. He has a marked hypotonic face, two hair whorls, bilateral ptosis, microstomia and a broad chest. His abilities were normal in the verbal domain (VIQ 71), but less preserved in performance (PIQ 54). He fulfils the DSM IV criteria for autism. Cerebral MRI is normal.
Cases 7 and 9 (46,XX,del(1)(p36.33p36.32)(2.1 Mb)) and (46,XX,del(21)(q22.13;q22.3)(6.6 Mb)), respectively, have been reported previously.35
They fulfil the DSM IV criteria for PDD‐NOS.
Case 12 (46,XY,dup (X)(q25)(3.2 Mb)) is a 24‐year‐old man born at term with standard neonatal measurements. At the age of 6 years, he developed a scoliosis that was surgically treated at 15 years of age. He fulfils the DSM IV criteria for autism.
Case 14 (46,XX, dup(1)(q31.1q31.2)(2.4 Mb)) is a 20‐year‐old woman born at term with normal neonatal measurements and Apgar score. She presented with motor milestones delay and has never been able to say a single word. Physical examination showed thin synophris and low‐set ears. She fulfils the DSM IV criteria for autism. Cerebral computed tomography scan is normal.
Case 16 (46,XY,del(7)(q11.22q11.23)(4.9 Mb)) is a 24‐year‐old man born at term with standard neonatal measurements. The diagnosis of Williams's syndrome had been proposed earlier in infancy but FISH study for 7 q11.2 deletion with a probe corresponding to elastin gene was normal. His motor and language milestones were delayed. He progressively developed spasticity. His growth parameters were normal. He had a hypospadias, a dorsolumbar scoliosis, and dysmorphic features with anteverted nares, long philtrum, malar hypoplasia and narrow palate. He loves music. He fulfils the DSM IV criteria for autism.
Case 28 (46,XX,dup (15)(q11.2q13.1)(4.6 Mb)) is a 25‐year‐old woman born at term with standard neonatal measurements and congenital hip dislocation. Her developmental milestones were delayed. She has developed epilepsy with polymorphic episodes since the age of 18 years. Her growth parameters were normal. She had dysmorphic features with a long thin face, anti‐mongoloid palpebral fissures, gothic palate and dentomaxillar dysharmonia. She fulfils the DSM IV criteria for autism. Her cerebral magnetic resonance imaging was normal.
Case 29 (46,XY,del(3)(q27.2q29)(8.8 Mb)) is a 14‐year‐old boy born at term with standard neonatal measurements. He had a narrow pelvis and chest with pectus carinatum. He developed severe dorsal kyphosis. Since birth, he has had feeding difficulties and his weight progressively decreased to −3 SD. He presented with dysmorphic features: triangular face, deep set eyes, gothic palate, micrognathia, abnormal helix and low neck hairline. He fulfils the DSM IV criteria for PDD‐NOS. Cerebral magnetic resonance imaging showed thick corpus callosum, megacisterna magna and accentuated Virchow–Robin spaces.