Heterozygous ADAR c.3019G>A pathogenic variant associated with variable neurological symptoms and incomplete penetrance in a fourgenerational family

Ann-Kathrin Bauer^1*Iris Marquardt²Benedikt Sundermann³Christine Wolf⁴Katrin Raupach⁵Kathrin Grundmann-Hauser⁵Laura Gieldon¹Maximilian Otterbach⁶Martin Maurer⁶Tobias Haack⁵Min Ae Lee-Kirsch⁴Georg-Christoph Korenke²Marc-Phillip Hitz¹

• ¹Institute of Medical Genetics, Carl von Ossietzky Universität Oldenburg, Oldenburg, Lower Saxony, Germany
• ²Department of Neuropediatrics, University Children’s Hospital, Klinikum Oldenburg, Oldenburg, Lower Saxony, Germany
• ³Institute of Radiology and Neuroradiology, Evangelisches Krankenhaus Oldenburg, Medical Campus, Carl von Ossietzky Universität Oldenburg, Oldenburg, Germany
• ⁴Department of Paediatrics, Faculty of Medicine Carl Gustav Carus, School of Medicine, Technical University Dresden, Dresden, Lower Saxony, Germany
• ⁵Institute of Human Genetics, University Hospital Tübingen, Tübingen, Germany
• ⁶Institute of Diagnostic and Interventional Radiology, Klinikum Oldenburg, Carl von Ossietzky Universität Oldenburg, Oldenburg, Germany

Heterozygous pathogenic variants in ADAR have been associated with dyschromatosis symmetrica hereditaria, while biallelic pathogenic variants have been associated with Aicardi-Goutières syndrome 6 (AGS6). However, the heterozygous variant c.3019G>A, (p.Gly1007Arg) has been described to cause neurological manifestations, which resemble AGS6 and are associated with an upregulation of interferon-stimulated genes.We report a four-generation family with two symptomatic family members and five unaffected carriers of the heterozygous pathogenic ADAR variant c.3019G>A. The index (patient 1) manifested a gait disorder at three years of age (weakness in his legs, a tendency to fall and hyperreflexia), dyslalia, and mild cognitive developmental delay. A paternal half-brother (patient 4) to patient´s father (patient 2) presented with irritability and regression of previous skills at the age of 6 months after a fever reaction, following the second routine hexavalent vaccination at the age of 4 months. At 20 years of age, the patient was wheelchair-bound, had spasticity and severe global development delay. A blood test in both patients showed increased interferon signature with activation of type 1-interferon. Five asymptomatic carriers were identified in this family (age range 2-81 years of age) nearly all of them (except the 81year old patient) showed a strong activation of type 1 interferon response in peripheral blood. Affected individuals had higher interferon signature than asymptomatic, underlining the possible role of interferon activation in disease mechanism.To our knowledge, this is the biggest family reported to date, encompassing a wide age-range of carriers, including an asymptotic carrier of advanced age (81 years of age).