title: Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations.
abstract: Biallelic mutations of UBE3B have recently been shown to cause Kaufman oculocerebrofacial syndrome (also reported as blepharophimosis-ptosis-intellectual disability syndrome), an autosomal recessive condition characterized by hypotonia, developmental delay, intellectual disability, congenital anomalies, characteristic facial dysmorphic features, and low cholesterol levels. To date, six patients with either missense mutations affecting the UBE3B HECT domain or truncating mutations have been described. Here, we report on the identification of homozygous or compound heterozygous UBE3B mutations in six additional patients from five unrelated families using either targeted UBE3B sequencing in individuals with suggestive facial dysmorphic features, or exome sequencing. Our results expand the clinical and mutational spectrum of the UBE3B-related disorder in several ways. First, we have identified UBE3B mutations in individuals who previously received distinct clinical diagnoses: two sibs with Toriello-Carey syndrome as well as the patient reported to have a "new" syndrome by Buntinx and Majewski in 1990. Second, we describe the adult phenotype and clinical variability 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 dysmorphic facial features. We conclude that UBE3B mutations cause a clinically recognizable and possibly underdiagnosed syndrome characterized by distinct craniofacial features, hypotonia, failure to thrive, eye abnormalities, other congenital malformations, low cholesterol levels, and severe intellectual disability. We review the UBE3B-associated phenotypes, including forms that can mimick Toriello-Carey syndrome, and suggest the single designation "Kaufman oculocerebrofacial syndrome".
authors.affiliation: Raphael Recanati Genetic Institute and Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, 49100, Petah Tikva, Israel, basel@post.tau.ac.il.
authors.forename: Lina
authors.initials: L
authors.lastname: Basel-Vanagaite
authors.forename: Rüstem
authors.initials: R
authors.lastname: Yilmaz
authors.forename: Sha
authors.initials: S
authors.lastname: Tang
authors.forename: Miriam S
authors.initials: MS
authors.lastname: Reuter
authors.forename: Nils
authors.initials: N
authors.lastname: Rahner
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Grange
authors.forename: Megan
authors.initials: M
authors.lastname: Mortenson
authors.forename: Patrick
authors.initials: P
authors.lastname: Koty
authors.forename: Heather
authors.initials: H
authors.lastname: Feenstra
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Farwell Gonzalez
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.forename: Julie
authors.initials: J
authors.lastname: Désir
authors.forename: Kwame
authors.initials: K
authors.lastname: Anyane-Yeboa
authors.forename: Christiane
authors.initials: C
authors.lastname: Zweier
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.forename: Tamison
authors.initials: T
authors.lastname: Jewett
authors.forename: Wenqi
authors.initials: W
authors.lastname: Zeng
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002784:Cholesterol / Q000097:blood; D004252:DNA Mutational Analysis; D005124:Eye Abnormalities / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D019066:Facies; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D017880:Limb Deformities, Congenital / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008831:Microcephaly / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D002784:Cholesterol; C482647:UBE3B protein, human; D044767:Ubiquitin-Protein Ligases