The Compassionate Side of Neuroscience: Tony Sermone’s Undiagnosed Genetic Journey—ADNP Mutation

J Mol Neurosci (2015) 56:751–757 DOI 10.1007/s12031-015-0586-6 The Compassionate Side of Neuroscience: Tony Sermone’s Undiagnosed Genetic Journey—ADNP Mutation Illana Gozes 1 & Celine Helsmoortel 2 & Geert Vandeweyer 2 & Nathalie Van der Aa 2 & Frank Kooy 2 & Sandra Bedrosian Sermone 3 Published online: 14 July 2015 # Springer Science+Business Media New York 2015 From the Editor Desk: the Compassionate Side of ADNP Some science: searching for brain protective proteins and aiming to unravel genes shaping our brains, at the turn of the century, we have published our first paper describing the cloning and characterization of a novel complementary DNA encoding a protein, which we called activity-dependent neuroprotective protein (ADNP) (Bassan et al. 1999). We went on to clone the human ADNP (hADNP) from a fetal brain cDNA library. Comparative sequence analysis of mouse and man indicated 90 % identity with the mouse (Zamostiano et al. 2001). Our recent analysis revealed high conservation and appearance only in vertebrates, indicating an important function in higher organisms, with a complex brain structure (Gozes et al. 2015). We further showed that the hADNP gene structure spans ~40 kilobases and includes five exons and four introns with alternative splicing of an untranslated second * Illana Gozes * Frank Kooy * Sandra Bedrosian Sermone 1 The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, Elton Laboratory for Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Adams Super Center for Brain Studies and Sagol School for Neuroscience, Tel Aviv University, Tel Aviv, Israel 2 Cognitive Genetics Group, Department of Medical Genetics, University of Antwerp, Antwerp, Belgium 3 ADNP Association, Phoenix, AZ, USA exon (chromosome 20q12-13.2, a region associated with aggressive tumor growth). As we eluded to in 2001 (Zamostiano et al. 2001), and later described in detail, hADNP is also mutated in cancer (Gozes et al. 2015). In an attempt to identify novel genes responsible for autism, a first de novo p.Lys408Valfs*31 mutation in the ADNP gene was identified in a large cohort of autistic patients (O’Roak et al. 2012b). Sequencing of the 209 families in this cohort did not reveal a second mutation in ADNP nor hardly in any other candidate gene; thus, a large-scale resequencing study was initiated (O’Roak et al. 2012a). In this study of 2446 probands, an additional p.Tyr719* de novo ADNP mutation was identified. By combining the data from WES and targeted resequencing studies initiated in multiple centers, Helsmoortel et al. (2014) identified a total of 10 patients with mutations in ADNP, including the two patients identified in both earlier studies. As all patients suffered from autism and shared characteristic facial features, it could be concluded that mutations in ADNP cause a syndromic form of autism. Remarkably, ADNP is one of a relatively small group of genes that appear to lead to autism in a substantial proportion of cases. Immediately following our initial report, two additional patients were identified that share many of the reported characteristics (Pescosolido et al. 2014; Vandeweyer et al. 2014). On top of that, Coe et al. (2014) reported five patients with a truncating ADNP mutation in a screening of 4716 patients with autism/ID. Most recently, De Rubeis et al. (2014) identified three more patients of a total of 3871 screened, and the DDD project reported four novel cases out of 1133 screened (Deciphering Developmental Disorders 2015). Taking advantage of mouse genetics, we have shown that ADNP is crucial for brain formation (Pinhasov et al. 2003) and learning and memory (Vulih-Shultzman et al. 2007), in a sex-dependent manner (Malishkevich et al. 2015; Kleiman et al. 2015). Using biochemical and cell biology techniques, 752 we showed multiple crucial interactions for ADNP, including the chromatin remodeling complex SWI/SNF (Mandel and Gozes 2007; Mandel et al. 2007), the RNA splicing machinery (Schirer et al. 2014), protein translation (Malishkevich et al. 2015), as well as the microtubule (Oz et al. 2014) and autophagy systems (Merenlender-Wagner et al. 2015). However, no good science can exist without listening and watching the society needs and hearing out the parents and wonderful caretakers of the ADNP children, which follows herein (Sandra Bedrosian Sermone, Our Undiagnosed Genetic Journey—ADNP mutation, 2015). Illana Gozes, Editor-in-Chief, Journal of Molecular Neuroscience The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, Elton Laboratory for Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Adams Super Center for Brain Studies and Sagol School for Neuroscience, Tel Aviv University, Israel. Celine Helsmoortel, Geert Vandeweyer, Nathalie Van der Aa, and Frank Kooy Cognitive Genetics Group, Department of Medical Genetics, University of Antwerp, Antwerp, Belgium. Tony Sermone ADNP Story Our Undiagnosed Genetic Journey—ADNP Mutation We had a 1.5-year-old daughter when we found out that we were going to have another baby. A few months later, we found out that we were actually having twins. Somewhere around month 7, I started having concerns because one of the baby’s heart rate would never go up during the routine stress test and that he was much less active than the other baby. This occurred many times, and I began to have a feeling that something was not right. My OB dismissed my concerns and said it was just the way they were Bsitting^ and assured me I was having a very healthy pregnancy and was right on track. After the boys were born by C-section, we were told that we had B2 healthy baby boys^ (Tony and Rocco). But as soon as I was brought into the room with them and was able to see them, I had a horrible gut feeling something was not right with Tony. I did not know what it was, I was happy they were born but had a strange feeling that he looked different. Within hours, we were told that during his exam, they heard a heart murmur that they had not detected while I was pregnant. They put him into the NICU and that is when the Bparent-panic^ set in. They explained the heart defect and told us it was not an emergency because many kids have murmurs when they are born, and they referred us to J Mol Neurosci (2015) 56:751–757 Doernbecher Children’s Hospital in 2 weeks. But I still had a horrible feeling something else was wrong. The more I would look at Tony, the more I felt like something was off. He just looked different, different than his twin brother, and different than his sister when she was born. I could not put my finger on it, but something looked off, and something looked strange to me. I did not think it was Down syndrome or anything specific at all, because I did not know what I thought. I had never had a friend or family member who had a child with a syndrome or any dramatic birt (...truncated)