A Case Report of Arrhythmia in <scp> <i>ZFHX3</i> </scp> ‐Related Neurodevelopmental Disorder

ZFHX3 (zinc finger homeobox 3) encodes a transcription factor that harbors 23 zinc fingers and 4 homeodomains and plays a role in myogenic and neuronal differentiation [1, 2]. ZFHX3 variants manifest as various phenotypes including atrial fibrillation with single nucleotide variants found in genome-wide studies, spinocerebellar ataxia 4 with GGC repeat expansion, partial seizures with biallelic variants, and neurodevelopmental disorders (NDD) with haploinsufficiency [2-5]. We report a patient harboring a novel heterozygous truncating variant of ZFHX3 manifesting developmental delay and atrial tachycardia. The patient was a 5-year-old female and the first child of healthy and nonconsanguineous parents. She was delivered at a gestational age of 40 weeks after an uneventful pregnancy, with a birth weight of 2905 g (−0.3 standard deviation [SD]), length of 48 cm (−0.8 SD), and occipitofrontal circumference (OFC) of 32.6 cm (−0.6 SD). She passed neonatal hearing screening, but showed patent ductus arteriosus (PDA), undergoing transcatheter closure at 11 months of age. Before the intervention for PDA, atrial tachycardia developed and was treated successfully by intravenous injection of flecainide at 11 months of age. Oral flecainide was administered until 21 months of age, and the arrythmia did not relapse without antiarrhythmic drugs. Feeding difficulties and hypotonia were noted, but tube feeding was not required. She was referred to our Institution at 1 year and 11 months of age for assessment. Her developmental milestones were as follows: head control at 4 months, sitting at 10 months, crawling at 11 months, and walking at 2 years and 10 months of age. Her developmental quotient was 49 at 3 years and 9 months of age. At referral, her height was 79.0 cm (−1.6 SD), weight was 9955 g (−0.9 SD), and OFC was 45.6 cm (−1.1 SD). Her dysmorphic features included hypopigmentation, square face, long eyelashes, and midface hypoplasia (Figure 1A). She revealed autism spectrum disorder and was able to speak several words at 3 years of age. The patient and family members were enrolled in an institutional review board–approved study at Kanagawa Children's Medical Center. Written informed consent for exome sequencing and for the use of the patient's photographs was obtained. Exome sequencing was performed as described previously, with a mean depth of coverage of 89.22 per base, and 94.2% of the coding region was covered by at least 20 reads [6, 7]. Exome sequencing identified a novel heterozygous variant in ZFHX3 (NM_006885.4:c.5206C>T p.(Gln1736*) NC_000016.10:g.72797476G>A) (Figure 1B). Trio Sanger sequencing confirmed the variant as de novo (Figure 1C). The variant is considered “pathogenic” according to the 2015 American College of Medical Genetics and Genomics variant interpretation guidelines (PVS1+PS2_supporting+PM2+PP3+PP4) [8]. Thus, we considered the patient as a ZFHX3-related NDD including developmental delay and autism spectrum disorders. The ZFHX3-related NDD was caused by heterozygous loss-of-function variants and demonstrated nonspecific neurodevelopmental features including various degrees of intellectual disability, autism spectrum disorder, and hypotonia [2]. Pathogenic variants have been identified previously and consist of deletions in 18 individuals and protein-truncating variants (PTVs) in 24 individuals, distributed throughout the gene, suggesting that haploinsufficiency underlies the pathogenesis [2]. The present patient developed arrhythmia, as well as PDA. Cardiovascular disease is uncommon and was observed in 5 of 18 (27.8%) individuals with deletions and in 3 of 28 (10.8%) individuals with PTVs, including septal defects in three patients, PDA in two patients, and arterial diseases in three patients [2]. Arrhythmia and tachycardia have not been described in previous patients and may be a rare complication of ZFHX3-related NDD. ZFHX3 has an association with heart rhythm disorders, and genetic variation in ZFHX3 is associated with atrial fibrillation (AF) in genome-wide studies [4, 9]. Susceptible variants are expression quantitative trait loci that decrease the expression of ZFHX3 in vitro experiments, leading to loss-of-function [10]. ZFHX3 participates in calcium homeostasis and mitochondrial function in atrial myocytes [11]. Cardiomyocyte-specific knockout mice of ZFHX3 show increased arrhythmia susceptibility, with alterations in cardiac conduction velocity, action potential duration, and calcium handling [10]. In our patient, haploinsufficiency of ZFHX3 is associated with atrial tachycardia. In conclusion, we report a patient with ZFHX3-related NDD complicated by arrhythmia and PDA. Cardiac rhythm disorder may be characteristic phenotypes of this NDD. This study was supported by The Initiative on Rare and Undiagnosed Diseases (grant number JP24ek0109760) from the Japan Agency for Medical Research and Development, MHLW Health Labour Sciences Research Grant (number 23FC1052), and JSPS KAKENHI Grant (number 25K19217). We thank the patient and her family for their cooperation. This work was supported by Japan Agency for Medical Research and Development, JP24ek0109760, MHLW Health Labour Sciences Research Grant, 23FC1052, and Japan Society for the Promotion of Science, 25K19217. The patient and family members were enrolled in an institutional review board-approved study with informed consent at Kanagawa Children's Medical Center. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.