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Five New Cases of Syndromic Intellectual Disability Due to KAT6A Mutations: Widening the Molecular and Clinical Spectrum

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Five New Cases of Syndromic Intellectual Disability Due to KAT6A Mutations: Widening the Molecular and Clinical Spectrum Urreizti et al. Orphanet Journal of Rare Diseases (2020) 15:44 https://doi.org/10.1186/s13023-020-1317-9 RESEARCH Open Access Five new cases of syndromic intellectual disability due to KAT6A mutations: widening the molecular and clinical spectrum Roser Urreizti1,2,3*† , Estrella Lopez-Martin2,4†, Antonio Martinez-Monseny5, Montse Pujadas6, Laura Castilla-Vallmanya1,2, Luis Alberto Pérez-Jurado2,6,7, Mercedes Serrano2,8, Daniel Natera-de Benito8, Beatriz Martínez-Delgado2,4, Manuel Posada-de-la-Paz2,4, Javier Alonso2,4, Purificación Marin-Reina9, Mar O’Callaghan8, Daniel Grinberg1,2†, Eva Bermejo-Sánchez4† and Susanna Balcells1,2† Abstract Background: Pathogenic variants of the lysine acetyltransferase 6A or KAT6A gene are associated with a newly identified neurodevelopmental disorder characterized mainly by intellectual disability of variable severity and speech delay, hypotonia, and heart and eye malformations. Although loss of function (LoF) mutations were initially reported as causing this disorder, missense mutations, to date always involving serine residues, have recently been associated with a form of the disorder without cardiac involvement. Results: In this study we present five new patients, four with truncating mutations and one with a missense change and the only one not presenting with cardiac anomalies. The missense change [p.(Gly359Ser)], also predicted to affect splicing by in silico tools, was functionally tested in the patient’s lymphocyte RNA revealing a splicing effect for this allele that would lead to a frameshift and premature truncation. Conclusions: An extensive revision of the clinical features of these five patients revealed high concordance with the 80 cases previously reported, including developmental delay with speech delay, feeding difficulties, hypotonia, a high bulbous nose, and recurrent infections. Other features present in some of these five patients, such as cryptorchidism in males, syndactyly, and trigonocephaly, expand the clinical spectrum of this syndrome. Keywords: KAT6A, Neurodevelopmental disease, Clinical genetics, Whole exome sequencing, Clinical characterization Background myeloid leukaemia (AML) [1]. KAT6A acetylates lysine- The lysine acetyltransferase 6A or KAT6A gene (a.k.a. 9 residues in histone H3 (H3K9), playing an essential MYST3 and MOZ; MIM *601408) codes for a member role in the regulation of transcriptional activity and gene of the histone acetyltransferase (HAT) family MYST. expression. KAT6A is also involved in the acetylation This gene was identified at a recurrent break-point of and regulation of the tumor suppressor p53, a key factor chromosomal translocations associated with acute in essential cell processes such as cell arrest and apop- tosis [2]. Moreover, KAT6A is able to directly bind and * Correspondence: [email protected] regulate the transcription factors Runx1 and Runx2 †Roser Urreizti, Estrella Lopez-Martin, Daniel Grinberg, Eva Bermejo-Sánchez through its C-terminal SM (serine and methionine rich) and Susanna Balcells contributed equally to this work. domain [3]. 1Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, IBUB, IRSJD, Barcelona, Spain De novo mutations in KAT6A have recently been asso- 2Centro de Investigaciones Biomédicas en Red de Enfermedades Raras ciated with a syndrome mainly characterized by intellec- (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain tual disability (autosomal dominant mental retardation Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Urreizti et al. Orphanet Journal of Rare Diseases (2020) 15:44 Page 2 of 14 32; MIM # 616268). To date, a total of 79 patients have fontanelle. At this follow-up visit developmental delay been reported [4–15]. All of them present with develop- and limb hypertonia were detected. The subject began to mental delay (DD) or intellectual disability (ID) with crawl at 4 years of age and made his first unassisted speech delay. Additionally, low muscle tone, problems steps at age 5. At 9 years of age absence seizures were with early feeding, and heart and eye defects are fre- clinically suspected and he was treated with valproate, quent [13]. Most of the reported mutations are loss of showing good response. At 11 years the treatment was function (LoF) variants including splicing mutations, discontinued as the patient did not present seizures any- stop gain, and frameshift changes. Recently, missense more and EEG was normal. Brain MRI (magnetic reson- mutations affecting highly conserved residues in relevant ance imaging) was always normal. He was also treated functional sites have also been described [12, 13]. with botulinum toxin because of hypersalivation due to The protein KAT6A is part of the MOZ/MORF com- dysphagia. The boy was also followed-up for severe my- plex together with ING5, KAT6B, MEAF6, and one of opia and constipation. He had a non-symptomatic large BRPF1–3. Neurodevelopmental syndromes have been as- atrial septal defect, ASD (ostium secundum type). sociated not only with KAT6A but also with KAT6B and At 10 years of age the dysmorphic traits continued, BRPF1. KAT6B mutations are associated with Say- suggestive of Opitz C syndrome. The patient presented Barber-Biesecker-Young-Simpson syndrome (SBBYSS, bulging eyes with true proptosis, mild epicanthus, hypo- MIM # 603736) and Genitopatellar syndrome (MIM # plastic nose, small mouth with normal philtrum and pal- 606170), while BRPF1 mutations associate with IDDDFP ate, and normal auricles (see detailed description in (Intellectual developmental disorder with dysmorphic fa- Table 1 and Fig. 1: a, g and l). From the neurological cies and ptosis, MIM # 617333). Like KAT6A syndrome, point of view he presented with spastic tetraparesis, with these two conditions present mainly with DD or ID and ulnar deviation of the hands, wide-base gait (increased speech delay, hypotonia, and midline facial dysmorphic distance between the tibial malleolus when walking) not features including a broad nose. in the range of a cerebellar ataxia but denoting clumsi- Here, we present five new unrelated cases bearing four ness and a subtle gait disturbance, and flexion of hips truncating mutations and one missense mutation in and knees. The patient lacks expressive language, but KAT6A, and we review the existing literature to expand has improved his ability to understand and to establish the clinical delineation of KAT6A syndrome. communication. He does not respond to simple com- mands and has poor attention span. He is unable to Results chew and is fed mashed food. He walks with increased Clinical description lift base and can take some steps alone. Usually, he The detailed phenotypic description of the patients is needs walker support to get around and has no sphincter summarized in Table 1. control. The patient is currently on physiotherapy and speech therapy, and pharmacological treatment with ris- Patient 1 (P1) peridone and methylphenidate due to behavioural dis- The patient is a 10-year-old boy from a non- turbances and ADHD (attention deficit-hyperactivity consanguineous and healthy couple. Two younger sib- disorder) traits, respectively. lings, a girl aged 5½ years and a boy aged 3, are healthy. During the pregnancy of the proband, intrauterine Patient 2 (P2) growth retardation was detected. He was born at 37 The patient is an 11-year-old boy, the first child of weeks by caesarean section with Apgar scores 9/10 at 1 healthy non-consanguineous parents. He was born at and 5 min, respectively. At birth, weight was 2.04 kg 38 + 5 weeks via caesarean section due to breech presen- (2nd percentile, − 2.04 SD), height 43 cm (<3rd percent- tation after an uneventful pregnancy. At birth, weight ile, − 2.91 SD), and cranial circumference 30 cm (<3rd was 2.97 kg (30th percentile, − 0.45 SD), length was 49 percentile, − 3.77 SD). The infant presented dysmorphic cm (25th percentile, − 0.28 SD), and cranial circumfer- features such a triangular facies, low-set ears, and short ence was 33 cm (10th percentile, − 0.61 SD). On neo- neck, in addition to cryptorchidism. Abdominal and cra- natal examination, sacral and suprasternal dimples were nial ultrasound studies were performed with no evidence observed on ultrasound with normal subjacent tissues of malformations. Serology for common neonatal infec- and reducible bilateral inguinal hernia. tions (toxoplasma, rubella, cytomegalovirus, and herpes The neonatal period was significant for poor feeding, simplex) as well as brain computerized tomography mild hypertonia of limbs, and delayed gross motor devel- (CT) and funduscopy were normal. opment. He achieved head control at 3 months, sitting at At the 5th month of life, a prominent metopic suture 15 months, and crawling and kneeling later than 24 was observed. The helical CT confirmed craniosynosto- months; currently he walks only with a walker. His sis of the metopic suture and ossification
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