Kabuki syndrome (KS) is one of the classical, clinically well-known multiple anomalies/mental retardation syndromes, mainly characterized by a very distinctive facial appearance in combination with additional clinical signs such as developmental delay, short stature, persistent fingerpads, and urogenital tract anomalies. In our study, we sequenced all 54 coding exons of the recently identified MLL2 gene in 34 patients with Kabuki syndrome. We identified 18 distinct mutations in 19 patients, 11 of 12 tested de novo. Mutations were located all over the gene and included three nonsense mutations, two splice-site mutations, six small deletions or insertions, and seven missense mutations. We compared frequencies of clinical symptoms in MLL2 mutation carriers versus non-carriers. MLL2 mutation carriers significantly more often presented with short stature and renal anomalies (p = 0.026 and 0.031, respectively), and in addition, MLL2 carriers obviously showed more frequently a typical facial gestalt (17/19) compared with non-carriers (9/15), although this result was not statistically significant (p = 0.1). Mutation-negative patients were subsequently tested for mutations in ten functional candidate genes (e.g. MLL, ASC2, ASH2L, and WDR5), but no convincing causative mutations could be found. Our results indicate that MLL2 is the major gene for Kabuki syndrome with a wide spectrum of de novo mutations and strongly suggest further genetic heterogeneity.

Maternal uniparental disomy for chromosome 14 [upd(14)mat] is associated with a characteristic phenotype including pre‐ and postnatal growth retardation, muscular hypotonia, feeding problems, motor delay, small hands and feet, precocious puberty and truncal obesity. Patients with upd(14)mat show features overlapping with Prader–Willi syndrome (PWS) and are probably underdiagnosed. Maternal upd(14) is frequently described in carriers of a Robertsonian translocation involving chromosome 14, but is also found in patients with a normal karyotype. Based on the above mentioned criteria we have identified six patients with upd(14)mat including two patients with a normal karyotype, one patient with a de novo Robertsonian translocation (14;21), one patient with a familial Robertsonian translocation (13;14) and two patients with a marker chromosome. In addition, we analyzed a cohort of 33 patients with low birth weight, feeding difficulties and consecutive obesity in whom PWS had been excluded by methylation analysis of SNRPN. In four of these patients (12%) we detected upd(14)mat. For rapid testing of upd(14)mat we analyzed the methylation status of the imprinted MEG3 locus. In conclusion, we recommend considering upd(14)mat in patients with low birth weight, growth retardation, neonatal feeding problems, muscular hypotonia, motor delay, precocious puberty and truncal obesity as well as in patients with a PWS like phenotype presenting with low birth weight, feeding difficulties and obesity. © 2006 Wiley‐Liss, Inc.

BackgroundIntellectual disability (ID) is often associated with behavioral problems or disorders. Mutations in the GRIN2B gene (MRD6, MIM613970) have been identified as a common cause of ID (prevalence of 0.5 – 1% in individuals with ID) associated with EEG and behavioral problems.MethodsWe assessed five GRIN2B mutation carriers aged between 3 and 14 years clinically and via standardized questionnaires to delineate a detailed behavioral phenotype. Parents and teachers rated problem behavior of their affected children by completing the Developmental Behavior Checklist (DBC) and the Conners’ Rating Scales Revised (CRS-R:L).ResultsAll individuals had mild to severe ID and needed guidance in daily routine. They showed characteristic behavior problems with prominent hyperactivity, impulsivity, distractibility and a short attention span. Stereotypies, sleeping problems and a friendly but boundless social behavior were commonly reported.ConclusionOur observations provide an initial delineation of the behavioral phenotype of GRIN2B mutation carriers.