UBE3B-related disorder is most widely known as Kaufman Oculocerebrofacial Syndrome (KOS; OMIM #244450), first described by Kaufman, Rimoin, Prensky and Sly in 1971 in four siblings of German ancestry. It has also been referred to as Blepharophimosis-Ptosis-Intellectual Disability syndrome (BPID), the name initially used when the gene was identified in 2012; Basel-Vanagaite and colleagues subsequently proposed unifying these descriptions under the single designation “Kaufman Oculocerebrofacial Syndrome.” It is caused by biallelic pathogenic variants in UBE3B(OMIM *608047), located on chromosome 12q24.11.
A brief naming history
The condition was first recognized purely on clinical grounds in 1971, and for the following four decades only a handful of additional cases were reported under the same name. In 2012, when the causative gene was identified, the discovering group described their patients as having a distinct entity they called blepharophimosis-ptosis-intellectual-disability (BPID) syndrome, not initially recognizing the overlap with Kaufman's original description. Once the molecular link became clear, the 2014 follow-up paper by the same group explicitly merged the two names, proposing “Kaufman Oculocerebrofacial Syndrome” as the single preferred term going forward; this is also the name used by GeneReviews and OMIM today. The two names are therefore synonymous and refer to the same condition, but “BPID” still appears in some of the literature, including the 2020 Egyptian cohort paper.
What does UBE3B normally do?
UBE3Bencodes ubiquitin-protein ligase E3B, an enzyme of the ubiquitin-proteasome system, the cellular machinery responsible for tagging proteins for degradation or for redirecting their trafficking. The protein contains an N-terminal IQ motif and a C-terminal HECT (Homologous to the E6-AP Carboxyl Terminus) domain that carries out the catalytic transfer of ubiquitin onto target proteins. UBE3B is the structural paralog of UBE3A, the gene disrupted in Angelman syndrome, underscoring the broader importance of this branch of the ubiquitin pathway in brain development. Ube3b-deficient mice show reduced viability, reduced body weight and brain , mild hearing impairment, and lowered cholesterol and cholesterol-precursor levels, closely mirroring the growth restriction, microcephaly, and hypocholesterolemia observed in affected patients.
Prevalence
UBE3B-related disorder is extremely rare. Since the gene was first linked to the disease in 2012, fewer than 50 patients have been reported worldwide, across families of Italian, Tunisian, Turkish, German, Mexican, American, Norwegian, Iranian, Egyptian, Bahraini, Jordanian origin, among others. The largest single series comes from Egypt (9 patients from 6 families), reported by Zaki and colleagues in 2020.
Inheritance
UBE3B-related disorder follows an autosomal recessive inheritance pattern. Parental consanguinity is reported in a substantial proportion of families.
Clinical characteristics
Patients present with a distinctive, age-evolving craniofacial gestalt (blepharophimosis, ptosis, upslanting palpebral fissures, sparse and laterally broad eyebrows, micrognathia, low-set or malformed ears with preauricular tags), progressive microcephaly, generalized hypotonia, and global developmental delay with intellectual disability that is usually moderate to severe. A characteristic neuroimaging finding is hypogenesis or near-complete agenesis of the corpus callosum.
Molecular characteristics
UBE3Bmutations are highly heterogeneous; most are nonsense, frameshift, or splice-site changes that truncate the protein before or within the HECT domain, although one specific recurrent variant has been repeatedly found in Egyptian families (see Molecular Characteristics).
Differential diagnosis
KOS belongs to a large and clinically overlapping group of disorders historically grouped as blepharophimosis-mental retardation (BMR) or blepharophimosis-intellectual disability (BID) syndromes – over 100 such entities have been described, many with unknown genetic cause. Conditions most often considered in the differential diagnosis include:
• Toriello-Carey syndrome (OMIM #217980): agenesis of the corpus callosum, facial anomalies, and Pierre Robin sequence; several patients originally diagnosed with this condition were later found to carry biallelic UBE3Bvariants and are now considered to have KOS
• Say-Barber/Biesecker/Young-Simpson (SBBYS) variant of Ohdo syndrome (OMIM #603736), caused by heterozygous KAT6Bvariants – a mask-like immobile face and bulbous nasal tip help distinguish it from the up-slanting palpebral fissures typical of KOS
• MED12-associated (X-linked) Ohdo syndrome / Maat-Kievit-Brunner syndrome(OMIM #300895)
• Dubowitz syndrome (OMIM #223370): primordial short stature, microcephaly, and eczema
• Smith-Lemli-Opitz syndrome (OMIM #270400): also features growth retardation, microcephaly, and low cholesterol, but is caused by a defect in cholesterol biosynthesis (DHCR7) rather than ubiquitination, and has its own distinct dysmorphic pattern
• Fraser syndrome (OMIM #219000): cryptophthalmos, syndactyly, and genital anomalies; was the initial working diagnosis in at least one reported family with KOS because of overlapping eye, ear, and genital findings
Because the facial gestalt of KOS becomes more distinctive with age and is easily overshadowed by these overlapping phenotypes in infancy, molecular confirmation by UBE3Bsequencing is recommended whenever this group of conditions is in the differential.
Genetic Counselling
As an autosomal recessive disorder, the recurrence risk for siblings of an affected proband with carrier parents is 25%. Prenatal diagnosis and preimplantation genetic testing are available once the familial UBE3Bvariant has been identified.
UBE3B