De Novo Duplication 7p21.1p22.2 in Autism Spectrum Disorder with Craniofacial Dysmorphism
Authors: Achandira Udayakumar Muthappa 
Published: July 2019

The duplication of short arm of chromosome 7 as de novo is extremely rare. Its phenotype spectrum varies depending on the region of duplication. We report a case of de novo duplication of chromosomal region 7p21.1p22.2 in a 3-year-old male child with autism. The patient was diagnosed with craniofacial dysmorphism, global developmental delay, hypotonia and bilateral cryptorchidism. This was detected by conventional G-banded karyotype/FISH and confirmed by array CGH. To the best of our knowledge, this is the first report of chromosomal region 7p21.1 involvement in a patient with autism spectrum disorder, showing features of 7p duplication phenotype. Identifying genes in the duplicated region involved using molecular techniques would promote characterize the phenotype and associated disease condition.

Duplication of 7p have been reported previously and the region/size varies among patients. The common features were craniofacial anomalies, large fontanelle, dysmorphism, psychomotor delay,5 and hypotonia was the most common complication observed. Review showed that 50% of 7p duplications were the result of balanced reciprocal translocation carriers. It could be an entire duplication of 7p in few or smaller but more terminal 7p in others.3 Arens et al reported complete 7p trisomy (without the involvement of any other chromosomes) in two patients.6 Similar diagnosis has been pursued in five other patients. 4,7 Many phenotypic features common of 7p duplication syndrome were present in our patient (Table I) as described in earlier reviews. 3,6,8 Noticeably, our patient did not have any cardiovascular abnormalities and thus showed better prognosis as compared to early deaths observed in previous reports. 3,6,8

Although evidences suggest that most 7p duplications occur due to malsegregation of parental balanced translocations or due to abnormal recombination of parental chromosome inversions; 2,3 few rare cases however result from de novo partial 7p direct duplication. The critical region however is assigned to 7p15 to pter for physical and mental abnormalities,2 and 7p21 for craniofacial dysmorphism. 3,9 Both these patient groups had many specific features in common. The range of severity might depend on the size and genes involved. It is suggested that genes GLI3(OMIM 165240; 7p13, HOXA13(OMIM 142959;7p15-7p14.2), TWIST (OMIM 601622; 7p21), CRS1(OMIM 123100; 7p21.3-7p21.2) and MEOX2 (OMIM 600535; 7p22.1-7p21.3) are associated with phenotype of 7p syndromes.1 A patient who had a microduplication at 7p22.1(1.7Mb) showed all the common craniofacial features and cryptorchidism, but global developmental delay and hypotonia was not observed,10 Although the region 7p22.1 contains 27 genes, 13 of which are OMIM-annotated, only one gene ACTB was the commonly observed in both their and our patient; which is likely to be the causative factor for features like hypotonia, global developmental delay and cryptorchidism. The databases like ODD and LOVD are useful for routine consultation in array diagnostics. Our patient who had a larger duplication (16.5Mb) showed global developmental delay and hypotonia in addition to craniofacial dysmorphism. The segmental size of duplication in our patient is relatively larger (16.5Mb) as compared to a few earlier reports,11 (Table I). An interesting clinical observation in our patient was its association with the ASD. Earlier, two reports had their 7p duplication associated with this disorder. One report is of an inverted duplication 7p14.1p11.2in an adult, 4 who lacked many characteristic features of the described 7p dup syndrome. This could possibly support that the critical region is distal. He was normocephalic, had normal milestones, meatal stenosis, bilateral esotropia and mild scoliosis. The other report was of autistic first cousins who carry two microduplications concordant with disease, one of whom had a tandem duplication on 7p21 that replicates part of the neurexophilin 1 and islet cell autoantigen 1 genes.12 Our patient was a child with direct duplication showing microcephalic and delayed milestones. None of the other features were present. But both these patients showed the autistic phenotype/behavioral features in common.The duplication was more proximal in previous case whereas it is distal in ours.

The region 7p21.1 to 7p22.2 observed in our patient has been suggested to be the critical region for the manifestations of the 7p duplication phenotype. This region of 7p contains the OMIM Morbid gene TWIST1 (OMIM*606122), duplications of which are thought to be the cause of the large fontanelles in these patients,13 and hence it is likely to be the cause of our patients clinical phenotype. The duplication region of our patient encompasses the whole of TWIST1,ICA1 (OMIM*147625) and NXPH1 (OMIM*604639) genes. These genes however are not directly disrupted by the breakpoints of this duplication. The array CGH analysis could not determine whether this duplication might have an effect on the regulation of these genes by way of a position effect. Parental chromosomal studies confirmed that our duplication was de novo and has not occured from a balanced chromosomal rearrangement, which sometimes might occur as insertional translocations, underlie 2.1% of the apparently observed de novo interstitial copy number changes detected by array CGH.14 Further molecular analysis is worth considering for those genes of the duplicated region particularly when they are associated with the autistic disorder phenotypes for further delineation of genotype-phenotype correlation.