Early onset Arboleda-Tham Syndrome due to KAT6A variants: Case report

Hongbo Chen^1,2,3Dan Yu^2,4,5Shanling Liu^2,4Hanbing Xie^4,6Lina Qiao^3,6Hanmin Liu^{10,11,12,6,7,8,9}Weiran Li^5,6*

• ¹Department of Medical Genetics/Prenatal Diagnostic Center, West China Second University Hospital, Sichuan University., Chengdu, China
• ²Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu., Sichuan, China
• ³Department of Pediatrics, West China Second University Hospital, Sichuan University., Chengdu, China
• ⁴Department of Medical Genetics/Prenatal Diagnostic Center, West China Second University Hospital, Sichuan University, Chengdu, China
• ⁵Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China
• ⁶Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, China
• ⁷Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China
• ⁸NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China
• ⁹Department of Pediatric Pulmonology and Immunology, WCSUH-Tianfu Sichuan Provincial Children's Hospital, Sichuan University., Meishan, China
• ¹⁰The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, Shanghai, China
• ¹¹West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan University, Chengdu, China
• ¹²Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China

Background: Arboleda-Tham syndrome (ARTHS), caused by likely pathogenic or pathogenic variants in the KAT6A gene, is characterized by developmental delay, distinctive facial dysmorphic features, and congenital cardiac anomalies. ARTHS warrants consideration in the differential diagnosis of neonates exhibiting unexplained cardiac arrhythmias, seizures, and dysmorphic features, although neonatal-onset manifestations remain underrecognized. Case: We report two Chinese patients with KAT6A variants diagnosed in the neonatal period who presented with life-threatening manifestations. Two unrelated neonates presented with severe cardiac arrhythmias or seizures within the first month of life, in association with congenital heart defects and developmental delay. Whole-exome sequencing (WES) identified two de novo KAT6A variants: a novel splice-site variant (c.3352+1G>C) in patient 1, who developed supraventricular tachycardia at 23 days of life, and a previously reported missense variant (c.4645G>A; p.Gly1549Ser) in patient 2 with seizures onset at 11 days. Both patients exhibited complex congenital heart disease (Patient 1: VSD, ASD and PDA; Patient 2: PFO and PDA), developmental delay, and characteristic dysmorphic features consistent with ARTHS. Conclusion: This report highlights the critical role of genomic sequencing in the diagnostic evaluation of neonates with unexplained cardiac arrhythmias or seizures. WES should be considered in neonates exhibiting severe early-onset multisystem involvement and dysmorphic features to investigate potential KAT6A variants. These findings substantially expand the phenotypic spectrum of ARTHS by documenting severe neonatal manifestations and contribute to a deeper understanding of KAT6A-related phenotypic variability.