Polysplenia and developmental delay in a case of microduplication in the 1p36.11 region involving the <i>ARID1A gene</i>

AT-rich interactive domain-containing protein 1A (ARID1A) is one of the main subunits of the switch/sucrose non-fermentable (SWI/SNF)-like chromatin remodeling complex, which contributes to human neuronal development. Microdeletion in the 1p36.11 region involving the ARID1A gene leads to Coffin–Siris syndrome resulting from haploinsufficiency.1 In contrast, a microduplication in the 1p36.11 region encompassing ARID1A has been reported in four patients with neurodevelopmental disorders, growth retardation, and other congenital anomalies of the ectodermal, skeletal, and gastrointestinal systems.2, 3 In this report, we report a patient with ARID1A duplication showing polysplenia, developmental delay, and multiple congenital anomalies. The propositus was a 2-year-old female and the third child of healthy non-consanguineous parents. Her parents and her elder siblings did not have any symptoms. She was delivered at a gestational age of 38 weeks after an uneventful pregnancy with a birthweight of 2434 g (−1.4 standard deviation [SD]), birth length of 46.0 cm (−1.3 SD), and occipital-frontal head circumference of 31.8 cm (−1.0 SD). She was referred to our department at the age of 14 months for assessment of developmental delay and polysplenia. At referral, her height was 68.6 cm (−2.5 SD), weight was 6.34 kg (−3.2 SD), and occipital-frontal head circumference was 40 cm (−2.9 SD). Her dysmorphic features were noted (Figure 1A). She controlled her head position at 4 months of age and sat at 11 months but was unable to crawl at 18 months of age. Moreover, due to moderate developmental delay (developmental quotient 51 by Enjoji scale at the age of 19 months), she spoke no words at the age of 2 years. Magnetic resonance imaging (MRI) of the head at 2 weeks of age was normal. Nevertheless, echocardiography showed the absence of the inferior vena cava with azygos continuation into the superior vena cava and no rhythmic abnormalities. Abdominal ultrasonography, a liver scan, and an upper gastrointestinal examination revealed a right-sided stomach, polysplenia, and no intestinal malrotation. Karyotype was 46,XX. The chromosomal microarray (GenetiSure Dx Postnatal Assay, Agilent, CA, USA) detected a 312 kb duplication in 1p36.11 from position 26 910 473 to 27 222 536 (GRCh37/hg19 assembly) (Figure 1B; Supplementary Materials). Duplicated regions included six RefSeq genes: ARID1A (MIM 603024), PIGV (MIM 239300), ZDHHC18, SFN (MIM 601290), GPN2, and GPATCH3 (MIM 617486). Parental samples were not obtained, so inheritance was unknown. We report the case of a patient carrying a microduplication in 1p36.11 with developmental delay and polysplenia. Microduplication in the 1p36.11 region has been reported in four patients with developmental delay, hypotonia, and microcephaly. The overlapping region delineated the minimal critical region (MCR) of 122 kb at 1p36.11, including ARID1A and part of the PIGV gene (Figure 1B). Table S1 indicates an overview of these four previous patients (PT1,2,3, and PT4) in addition to the patient featured in this report (PT5). The patient presented in the report shares some clinical features such as developmental disorders, language delay, and hypotonia; however, polysplenia has never been noted in previously reported patients. Polysplenia might be a novel phenotype of ARID1A duplication, especially considering that none of the six duplicated genes in this region have been associated with polysplenia or other laterality sequences. The genetic basis of polysplenia, a type of heterotaxy characterized by laterality defects, is highly heterogeneous and remains unclear. Previous studies have identified various genetic causes for heterotaxy, including chromosomal aneuploidies (trisomy 13 and 18) and other chromosomal abnormalities.4 Furthermore, at least 25 genes associated with laterality defects have been identified, primarily involved in NODAL/TGF beta signaling, SHH signaling, and monocilia function.5 However, each gene contributes only a small percentage to the overall genetic basis of laterality defects, and causative variants have been found in approximately 7.1% of cases.5 Incomplete penetrance further complicates efforts to elucidate the genetic basis of these defects. ARID1A duplication may be another genomic disorder associated with laterality defects. A previous patient with this microduplication exhibited four-limb postaxial polydactyly, a condition categorized as a laterality or polarity disorder.2 Notably, four-limb postaxial polydactyly has also been observed in primary ciliary dyskinesia, a ciliopathy associated with laterality defects, as well as other ciliopathies such as Ellis-van-Creveld, Jeune, and Meckel syndrome.6 This suggests that heterotaxy and postaxial polydactyly may be part of the same spectrum of laterality sequences. The overlapping duplicated region in both the present and the previous patients involves ARID1A and PIGV (Figure 1B). Interestingly, ARID1A interacted with TGF beta signaling in tumor cells, and ARID1A knockdown has been shown to reduce this signaling related to laterality defects.7 Our report adds ARID1A duplication to the list of potential genetic causes of laterality defects. In conclusion, we present a patient with developmental delay and polysplenia harboring ARID1A duplication. This report suggests that ARID1A duplication syndrome may impact laterality. We would like to thank the patient and her family for their cooperation. The authors declare no conflict of interest. The patients and family members were enrolled in an institutional review board-approved study at the Tokyo University Hospital after obtaining an informed consent. Data S1. Table S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.