Disruption of the IL1RAPL1 gene associated with a pericentromeric inversion of the X chromosome in a patient with mental retardation and autism

To the Editor: Defects in a number of genes distributed on the human X chromosome have been associated with mental retardation (MR) and developmental delay (DD) (1–3). We have evaluated a 7-yearold boy with global DD, autism, facial dysmorphism and a pericentromeric inversion of the X chromosome. The patient was a full-term infant born to a 25-year-old female with mild MR (Fig. 1a). At age 7 years 9 months, the patient’s weight was 23 kg (30th centile), his height was 125 cm (40th centile) and his head circumference was 51 cm (20th centile). He had a frontal hair upsweep, increased inner canthal measurement (98th centile) and outer canthal measurement (97th centile), mildly upslanted palpebral fissures, thickened ears with upturned lobes, and a short nose with thickening of the alae nasi and columella (Fig. 1b). His midface gave a hypotonic appearance with an open mouth and tented upper lip. The lower teeth were crowded anteriorly. Diminished muscle tone with low strength was noted. He also had hyperreflexia of the lower limb but no clonus. On the Autism Diagnostic Observation Scale (ADOS) and the Childhood Autism Rating Scale, the patient scored well within the autism range [http://www.agre. org/ and (4)]. He received a composite score of 31 on the Vineland Adaptive Behavior Scale (Interview Edition), indicative of marked impairment. The patient’s mother experienced a severe varicella infection and associated fever, a seizure, and cerebrospinal fluid pleocytosis in infancy. She had an intelligence quotient of 69. Among the areas assessed, she had greater difficulty with reception and expression of verbal skills. She has also been diagnosed as having autism spectrum disorder using the ADOS. The patient’s grandmother was reported to be clinically normal. Routine chromosome analysis in the patient and his mother showed 46,Y,inv(X)(p22.1q13) and 46,X,inv(X)(p22.1q13) karyotypes, respectively (Fig. 1a). Grandmother had a normal 46, XX karyotype. X-inactivation studies showed a random X-inactivation pattern for both women (Fig. 1a). We mapped the Xp breakpoint to within the IL1RAPL1 gene in the patient and his mother. Clone RP4-653H3, containing exon 3 and the flanking introns of the IL1RAPL1 gene, spanned the Xp22.1 breakpoint (Fig. 1c–e). Southern blot analysis with a cDNA probe spanning exons 3 and 4 of IL1RAPL1 gave a normal restriction pattern in the patient (data not shown). Thus, the Xp breakpoint was inferred to lie in intron 2 of IL1RAPL1, a region of approximately 60 kb upstream of exon 3. The Xq13 inversion breakpoint was mapped between two clones, RP11-580P8 and RP11402P6 (Fig. 1g). Southern hybridization analysis was performed using an ACRC cDNA probe (exons 2–8) and a probe containing the entire coding region of CXCR3. Both probes gave normal restriction patterns in the patient (data not shown). Furthermore, we amplified a genomic fragment covering approximately 13 kb between the exon 21 of OGT and exon 2 of ACRC in the patient (data not shown). Altogether, these results suggest that the Xq13 breakpoint is likely to be located in the 40 kb genomic region flanking the CXCR3 gene. The Xq13 breakpoint interval contains several known genes (OGT, ACRC, CXCR3, KIAA2001 and RPS4X) (Fig. 1g). Reverse transcriptase-polymerase chain reaction analysis detected no loss of expression of these genes in the patient (data not shown). IL1RAPL1 has previously been shown to be disrupted/deleted or mutated in some patients