Microduplication 22q11.2 in a child with autism spectrum disorder: clinical and genetic study


* Correspondence to first author at Department of Paediatrics, Ospedale San Giovanni, CH-6500 Bellinzona, Switzerland.
E-mail: gianpaolo.ramelli@eoc.ch


Microduplication of the 22q11.2 chromosomal region has been recognized since 1999 and has been associated with a highly variable phenotype. Neurodevelopmental impairment and behavioural problems are very common in patients with 22q11.2 duplication. Autism spectrum disorders (ASDs) have previously been reported in only two patients with 22q11.2 duplication and striking dysmorphic features. We report here on a 4-year-old male of healthy consanguineous parents presenting with ASD according to DSMIV, revised, criteria as a primary manifestation. The child walked at 16 months and started to say one word and some sounds. Parents noticed a subsequent developmental arrest. At 4 years his functional development age, evaluated by the Psychoeducational Profile, was roughly 6 months. Mild non-specific facial dysmorphism was noted. Genetic analyses of the child demonstrated a de novo microduplication of the 22q11.2 chromosomal region. This genetic anomaly was best seen in interphases of blood lymphocytes and in buccal smear nuclei. Our case illustrates once again the clinical heterogeneity of the 22q11.2 duplication as well as the wide genetic complexity of ASD. We suggest that genetic evaluation of ASD should include fluorescence in-situ hybridization analysis of the 22q11.2 chromosomal region.

It is widely assumed that the autism spectrum disorders (ASDs), as defined by the revised DSM-IV,1 are largely genetic in origin. Despite substantial research over the past decade, the susceptibility of genetic and/or epigenetic factors has remained remarkably elusive, probably because of the wide genetic and clinical heterogeneity of ASD. Microduplication of the 22q11.2 chromosomal region and the highly variable phenotype associated with it have been recognized since 1999.2 Although neurodevelopmental impairment and behavioural problems are very common in patients with 22q11.2 duplication, ASD as the presenting manifestation has been recently reported in two patients with clearly dysmorphic features.3,4

Case report

A 4-year-old male was referred for neuropaediatric evaluation because of developmental delay and autistic behaviour. The proband was the second child of healthy consanguineous parents. Family history was negative for autism. The child was born at 34 weeks', gestational age by elective Caesarean section. Pregnancy was uneventful. His birthweight was 1855g (50th centile) and length 46cm (90th centile). Early developmental milestones were within normal limits. The child walked at 16 months and started to say one word and some sounds. Parents noticed a subsequent arrest of development. At the age of 4 years the child was restless and unable to speak; he could not establish eye contact nor play with toys. Physical examination at that age revealed a height of 99cm, a weight of 14kg, and a head circumference of 51cm. These are 3rd, 3rd, and 25th–50th centiles for age respectively. Mild facial anomalies include high forehead, broad nasal bridge, and micrognathia. Ears and palate were normal, as were genitalia and palmar flexion creases. Pulmonary and cardiovascular systems were normal.

Psychiatric evaluation revealed a properly dressed, but restless and inattentive child. He wandered around the examination room and was unable to communicate with the observer. He had no verbal communication skills and he used his mouth for recognition of the objects he was offered. He was not interested in toys and avoided contact with other children. The Childhood Autism Rating Scale5 and Autism Diagnostic Observation Scale6 were used to evaluate the severity of his autistic symptoms. His total Childhood Autism Rating Scale score was 43.5 (indicating severe autism) and Autism Diagnostic Observation Scale was 48. He was diagnosed with autistic disorder according to DSM-IV criteria for autistic syndrome. He showed severe lack of social interaction, shared attention, and absence of social imitation games; he also showed restricted and repetitive patterns of behaviour and arm movements.

His language, social development, and motor coordination were well below his age level. Even when requested, he displayed no ability to talk or any desire to communicate. He also did not respond to attempts to play and made no eye contact with people around him. His functional developmental age was approximately 6 months, evaluated through the Psychoeducational Profile – Revised,7 with various results in different areas and, consequently, a disharmonic profile. He showed the best results in imitation, and global and fine motor skills. The worst performances were in oculo-manual integration and cognitive verbal items, in accordance with autistic profiles. All laboratory tests were normal, e.g. metabolic, serological investigations for toxoplasmosis, rubella and cytomegalovirus, plasma levels of calcium, phosphorus, uric acid, and magnesium. Electroencephalogram and magnetic resonance images of the brain were normal.

Cytogenetic and fluorescence in-situ hybridization analyses

For cytogenetic analysis, blood samples from the patient and the parents were processed by standard laboratory protocols for chromosomes. Flourescent in-situ hybridization (FISH) was performed with probes for the Di Giorge/velo-cardio-facial syndromes critical region TUPLE1 and 25 (Vysis, Downers Grow, IL, USA). Interphase FISH on buccal smears was also performed in the child and the parents using the same probes. The patient had a 46, XY male karyotype. FISH analysis of metaphases revealed a duplication of TUPLE1 probe on one chromosome 22q (Fig. 1). The duplication of 22q11.2 region was confirmed on interphases of lymphocytes and buccal smears nuclei. Chromosome and FISH analyses of both parents were normal. Fragile X test was negative.

Figure 1.

 Interphase cells showing duplication of TUPLE1 within the DiGiorge/velo-cardio-facial syndromes chromosomal region. Two control probes (ARSA) signals are also present.

Parental informed consent was given for genetic analyses and for publication of information used in this report.


ASD is a common yet complex neurodevelopmental condition with a strong genetic component, as established by heritability estimates of up to 90%.8,9 Several recognizable genetic syndromes display various degrees of ASD features; however, such syndromes are present in fewer than 10% of patients with ASD. Structural anomalies, mainly of chromosome 15, and more occasionally of chromosome 7, have been described in ASD.10 Such chromosome structural abnormalities have been used to identify genes potentially involved in the pathogenesis of ASD. Microdeletions of chromosome 22 region 22q11.2 cause the DiGeorge/velocardiofacial syndrome, which represents a spectrum of clinical anomalies including congenital heart defects and immunological and endocrinological abnormalities. Neurological and psychiatric features are very common among these patients. In a very recent survey, ASD was present in 50% of children with 22q11.2 deletion.11

The microduplication of 22q11.2, which represents the complementary genomic disorder of the 22q11.2 deletion, was first reported by Edelman et al. in a 4-year-old female with mild dysmorphism, velopharyngeal insufficiency, and developmental delay.2 Ensenauer et al. reported 10 unrelated patients with 22q11.2 duplication whose phenotype showed a wide range of features including velopharyngeal insufficiency, heart defects, and urogenital abnormalities.12 Behavioural defects, some degree of intellectual disability and neuropsychological problems were also present. In a recent review, de La Rochebrochard et al. summarized the clinical and molecular findings of almost 50 reported patients, confirming the broad clinical heterogeneity of the condition.13 Although neurodevelopmental impairment and behavioural problems were common, no patients presented with ASD.

There are two previously reported cases of 22q11.2 duplication with ASD features.3,4 In both cases, however, genetic analyses were performed because of facial dysmorphism and cardiovascular anomalies. In contrast, in our patient, ASD was the genuine clinical presentation, as the child had neither significant dysmorphism nor cardiac malformations. Our case illustrates once again the clinical heterogeneity of the 22q11.2 duplication as well as the wide genetic complexity of ASD. Also, parental consanguinity was observed in a recently published case, opening the possibility that an additional recessive mutation could contribute to the observed ASD phenotypes.4 This hypothesis, however, is not supported by the papers of De Braekeleer et al. and Jorde et al., which indicated that a single recessive gene was unlikely to be involved in ASD.14,15 As a result of the wide clinical heterogeneity, the 22q11.2 microduplication may be largely undetected.16 For this reason, genetic evaluation of ASD should include FISH analysis of the 22q11.2 chromosomal region.