Recurrent De Novo Mutations Disturbing the GTP/GDP Binding Pocket of RAB11B Cause Intellectual Disability and a Distinctive Brain Phenotype.

The Rab GTPase family comprises ∼70 GTP-binding proteins, functioning in vesicle formation, transport and fusion. They are activated by a conformational change induced by GTP-binding, allowing interactions with downstream effectors. Here, we report five individuals with two recurrent de novo missense mutations in RAB11B; c.64G>A; p.Val22Met in three individuals and c.202G>A; p.Ala68Thr in two individuals. An overlapping neurodevelopmental phenotype, including severe intellectual disability with absent speech, epilepsy, and hypotonia was observed in all affected individuals. Additionally, visual problems, musculoskeletal abnormalities, and microcephaly were present in the majority of cases. Re-evaluation of brain MRI images of four individuals showed a shared distinct brain phenotype, consisting of abnormal white matter (severely decreased volume and abnormal signal), thin corpus callosum, cerebellar vermis hypoplasia, optic nerve hypoplasia and mild ventriculomegaly. To compare the effects of both variants with known inactive GDP- and active GTP-bound RAB11B mutants, we modeled the variants on the three-dimensional protein structure and performed subcellular localization studies. We predicted that both variants alter the GTP/GDP binding pocket and show that they both have localization patterns similar to inactive RAB11B. Evaluation of their influence on the affinity of RAB11B to a series of binary interactors, both effectors and guanine nucleotide exchange factors (GEFs), showed induction of RAB11B binding to the GEF SH3BP5, again similar to inactive RAB11B. In conclusion, we report two recurrent dominant mutations in RAB11B leading to a neurodevelopmental syndrome, likely caused by altered GDP/GTP binding that inactivate the protein and induce GEF binding and protein mislocalization.

Haploinsufficiency of MEIS2 is associated with orofacial clefting and learning disability.

MEIS2 is a homeodomain-containing transcription factor of the TALE superfamily that has been proven important for development. We confirm and extend a recent single clinical report stating that deletions in MEIS2 can cause cleft palate [Crowley et al. (2010); Am J Med Genet 152A:1326-1327]. Here we report on five additional patients with 15q14 deletions of sizes 0.6, 0.6, 1.0, 1.9, and 4.8 Mb, respectively, all involving MEIS2. In addition, we present a family with four affected individuals and an intragenic 58 kb direct duplication disrupting MEIS2. In total, 7/9 cases had clefting, from mild (submucous cleft palate) to severe (cleft lip and palate), and 3/9 cases had ventricular septal defects. All cases had delayed motor development and most had learning disability, at worst in the mild intellectual disability range. The cases had overlapping facial features (broad forehead, finely arched eyebrows, mildly shortened philtrum, and tented upper lip) but individually they were not considered to be dysmorphic. Our results show that MEIS2 is a gene needed for palate closure. In syndromic cases of cleft palate, MEIS2 should be considered among the candidate genes, for example, in cases without 22q11.2 deletions.

Registration of Down syndrome in the Medical Birth Registry of Norway: validity and time trends.

OBJECTIVE: To validate Down syndrome registration in the Medical Birth Registry of Norway (MBRN), 2001-2005, and study time trends and geographical differences in Down syndrome prevalence,1967-2005. DESIGN/SETTING: Population-based cohort study, Norway. POPULATION: 2.3 million pregnancies and births registered in the MBRN, 1967-2005. METHODS: We linked data from the MBRN during 2001-2005 with data from Norway's four laboratories of medical genetics. We calculated sensitivity and positive predictive values (PPV) of the MBRN registration overall, and by background variables. Prevalence rates from 1967 to 2005, overall and regional, were presented graphically as smoothed lowess estimates, crude and standardized for maternal age. Time trends were evaluated, adjusting for maternal age by logistic regression. MAIN OUTCOME MEASURES: Sensitivity, PPV, and prevalence rates. RESULTS: Five hundred and seventy-six verified cases of Down syndrome gave a prevalence of 2.0 per 1,000 among 288,213 births and terminations in the MBRN during 2001-2005. Of verified cases, 470 (81.6%) were registered with Down syndrome in the MBRN, while 470 (90.2%) of 521 MBRN-registered cases were verified. Sensitivity was higher in the Northern (93.1%; p=0.005) and Middle (90.6%; p=0.02) region relative the Southern (76.3%), higher for mothers > or =35 years (92.9%) than younger ones (86.1%; p=0.01), and higher for live births (88.8%) relative stillbirths (55.6%; p<0.001). When adjusting for maternal age, there were no significant time trends in prevalence rates from 1967 to 2005. Regional differences over time were found, probably representing reporting differences. CONCLUSIONS: Validity of registration in the MBRN was satisfactory during 2001-2005. Increasing prevalence rates over time were explained by increasing maternal age.

Monosomy 8 rescue gave cells with a normal karyotype in a mildly affected man with 46,XY,r(8) mosaicism.

The psychomotor and somatic development from early childhood into adult life is described in a man with 46,XY,r(8)/46,XY mosaicism. The ring chromosome 8 appeared to be of normal length on G-banding, but terminal deletions on 8q and 8p were detected with FISH and CGH. By STR marker analysis the 8p deletion proved to be quite large, at least 6.74 Mb, while the 8q deletion was small, around 2.5 Mb. The haplotype analysis also demonstrated that the r(8) originated from a maternal chromosome 8, and that cells with normal male karyotype resulted from monosomy 8 rescue after loss of the ring 8, i.e. a mitotic duplication of the paternal chromosome 8. The patient has a mild phenotype with no malformations and mild mental retardation, also compared to other ring chromosome 8 patients. His clinical condition has remained stable for the last 20 years.