View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by RERO DOC Digital Library Hum Genet (2014) 133:939–949 DOI 10.1007/s00439-014-1436-2 ORIGINAL INVESTIGATION Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations Lina Basel-Vanagaite · Rüstem Yilmaz · Sha Tang · Miriam S. Reuter · Nils Rahner · Dorothy K. Grange · Megan Mortenson · Patrick Koty · Heather Feenstra · Kelly D. Farwell Gonzalez · Heinrich Sticht · Nathalie Boddaert · Julie Désir · Kwame Anyane-Yeboa · Christiane Zweier · André Reis · Christian Kubisch · Tamison Jewett · Wenqi Zeng · Guntram Borck Received: 16 December 2013 / Accepted: 25 February 2014 / Published online: 11 March 2014 © Springer-Verlag Berlin Heidelberg 2014 Abstract Biallelic mutations of UBE3B have recently additional patients from five unrelated families using either been shown to cause Kaufman oculocerebrofacial syn- targeted UBE3B sequencing in individuals with sugges- drome (also reported as blepharophimosis–ptosis–intellec- tive facial dysmorphic features, or exome sequencing. Our tual disability syndrome), an autosomal recessive condition results expand the clinical and mutational spectrum of the characterized by hypotonia, developmental delay, intellec- UBE3B-related disorder in several ways. First, we have tual disability, congenital anomalies, characteristic facial identified UBE3B mutations in individuals who previously dysmorphic features, and low cholesterol levels. To date, received distinct clinical diagnoses: two sibs with Toriello– six patients with either missense mutations affecting the Carey syndrome as well as the patient reported to have a UBE3B HECT domain or truncating mutations have been “new” syndrome by Buntinx and Majewski in 1990. Sec- described. Here, we report on the identification of homozy- ond, we describe the adult phenotype and clinical variabil- gous or compound heterozygous UBE3B mutations in six ity of the syndrome. Third, we report on the first instance of homozygous missense alterations outside the HECT domain of UBE3B, observed in a patient with mildly dys- L. Basel-Vanagaite and R. Yilmaz contributed equally. morphic facial features. We conclude that UBE3B muta- tions cause a clinically recognizable and possibly under- Electronic supplementary material The online version of this diagnosed syndrome characterized by distinct craniofacial article (doi:10.1007/s00439-014-1436-2) contains supplementary material, which is available to authorized users. L. Basel-Vanagaite (*) M. S. Reuter · C. Zweier · A. Reis Raphael Recanati Genetic Institute and Felsenstein Medical Institute of Human Genetics, Friedrich-Alexander-Universität Research Center, Rabin Medical Center, Beilinson Campus, Erlangen-Nürnberg, 91054 Erlangen, Germany 49100 Petah Tikva, Israel e-mail: [email protected] N. Rahner Medical Faculty, Institute of Human Genetics, University L. Basel-Vanagaite of Dusseldorf, 40225 Dusseldorf, Germany Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel D. K. Grange Division of Genetics and Genomic Medicine, Department L. Basel-Vanagaite of Pediatrics, Washington University School of Medicine, Pediatric Genetics, Schneider Children’s Medical Center St. Louis Children’s Hospital, St. Louis, MO 63110, USA of Israel, 49202 Petah Tikva, Israel M. Mortenson · P. Koty · T. Jewett R. Yilmaz · C. Kubisch · G. Borck (*) Department of Pediatrics, Section on Medical Genetics, Wake Institute of Human Genetics, University of Ulm, Forest School of Medicine, Winston-Salem, NC 27157, USA 89081 Ulm, Germany e-mail: [email protected] H. Feenstra Roosevelt Hospital, New York, NY 10019, USA S. Tang · K. D. Farwell Gonzalez · W. Zeng Ambry Genetics, Aliso Viejo, CA 92656, USA 1 3 940 Hum Genet (2014) 133:939–949 features, hypotonia, failure to thrive, eye abnormalities, Silfhout et al. 2013), and Dubowitz syndrome (MIM other congenital malformations, low cholesterol levels, and 223370) (reviewed by Verloes et al. 2006). severe intellectual disability. We review the UBE3B-asso- Only six patients with KOS/BPID syndrome and bial- ciated phenotypes, including forms that can mimick Tori- lelic UBE3B mutations have been described previously ello–Carey syndrome, and suggest the single designation (Basel-Vanagaite et al. 2012; Flex et al. 2013). Here, we “Kaufman oculocerebrofacial syndrome”. describe six additional patients and review the clinical and molecular spectrum of this recognizable entity. Introduction Methods Kaufman oculocerebrofacial syndrome (KOS; MIM 244450) is an autosomal recessive disorder character- Patient ascertainment and clinical evaluations ized by developmental delay and intellectual disability (ID), microcephaly, hypotonia, structural eye anoma- The study was approved by the Ethics Committees of the lies and other organ malformations, as well as distinctive Universities of Ulm and Erlangen-Nürnberg, and written facial dysmorphic features. Fewer than 10 affected indi- informed consent was obtained from the patients’ parents viduals had been reported from the first description in or legal guardian. We report on six individuals from five 1971 to 2012 (Kaufman et al. 1971; Figuera et al. 1993; unrelated families. The affected individuals were evaluated Garcia-Cruz et al. 1988; Dentici et al. 2011) when we by routine medical history interviews and a physical exami- redescribed the syndrome (under the acronym BPID syn- nation, and clinical records were reviewed. All six patients drome, blepharophimosis–ptosis–intellectual disability had undergone brain imaging [magnetic resonance imaging syndrome; MIM 615057) and identified biallelic UBE3B (MRI) in patients 1-5 and computed tomography in patient mutations as the underlying cause (Basel-Vanagaite et al. 6], and the MRI scans were reviewed by one radiologist 2012). In that report, patients with BPID syndrome were (N.B.). A basic endocrinological evaluation had been per- thought to have a distinctive condition because they lacked formed in all affected individuals. the eye abnormalities characteristic to patients with KOS, In patients 1–3, KOS was not regarded as a differential such as microphthalmia and optic nerve anomalies. There diagnosis and mutations were identified following clinical is a phenotypic overlap between KOS, Toriello–Carey syn- diagnostic or research exome sequencing. After the reports drome (TCS; agenesis of the corpus callosum with facial on UBE3B mutations as the cause of KOS (Basel-Vanagaite anomalies and Pierre-Robin sequence; MIM 217980; Tori- et al. 2012; Flex et al. 2013) the attending geneticists of ello et al. 2003) and the phenotype reported by Buntinx patients 1–3 contacted L.B.-V. and G.B. UBE3B mutations and Majewski as a “new” syndrome in 1990 (Buntinx and were suspected in patients 4–6 based mainly on facial dys- Majewski 1990). The differential diagnosis of KOS and morphic features following a literature review performed related syndromes extends to other blepharophimosis– by one of the authors (L.B.-V.) although these three chil- intellectual disability syndromes (or Ohdo-like syndromes) dren had previously received clinical diagnoses different such as Ohdo syndrome (MIM 249620), KAT6B-associated from KOS/BPID. Patients 4 and 5 are siblings and have Say-Barber/Biesecker/Young-Simpson syndrome (MIM been reported with a diagnosis of typical TCS (Toriello 603736; Clayton-Smith et al. 2011), MED12-associated et al. 2003); and patient 6 was reported by Buntinx and Maat-Kievit-Brunner syndrome (MIM 300895; Vulto-van Majewski (1990). Exome and Sanger sequencing H. Sticht Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany UBE3B mutations were identified by whole exome sequencing in patients 1–3 and by Sanger sequencing of N. Boddaert the coding exons and exon–intron boundaries in patients Department of Pediatric Radiology, Hôpital Necker, Enfants 4–6. After the identification of a mutation in a sibling pair Malades and Medical Faculty, Université Paris Descartes, 75015 Paris, France with a previous diagnosis of TCS, we sequenced UBE3B in four additional unrelated patients with TCS, two of whom J. Désir have been reported previously (Toriello et al. 2003). Exome Institut de Pathologie et de Génétique, 6041 Gosselies, Belgium sequencing was performed using the SureSelect Human All Exon 50 Mb Kit (Agilent) and a paired-end proto- K. Anyane-Yeboa Columbia University Medical Center, New York, NY 10010, col on an Illumina HiSeq 2000 sequencer (patients 1 and USA 3) or a SOLiD 5500xl instrument (patient 2). Reads were 1 3 Hum Genet (2014) 133:939–949 941 Fig. 1 Facial features of the individuals described in this study. The numbers correspond to the numbers in Table 1. Ages of the patients are as follows: 1, 33 years; 2A, 8 months; 2B, 5 years 6 months; 3A, 4 months; 3B, 2 years; 4, 16 years; 5, 10 years 8 months; 6, 25 years aligned to the human genome assembly hg19 (GRCh37) Patient 1 (Fig. 1, picture 1; Table 1) is a 33-year-old man and variants were called and annotated using software inte- with profound ID and no speech. He is the second son (of grated in the respective in-house exome analysis pipeline three) born to unaffected parents of Hispanic ancestry who as described previously [Gandomi et al. 2013, for patients are second cousins once removed. He presented at birth 1 and 3; Hansen et al. 2013 (patient MR043), for patient with muscular hypotonia and hearing impairment. Unlike 2]. This resulted in a mean