Identification of C12orf4 as a gene for autosomal recessive intellectual disability.

Intellectual disability (ID) is a major health problem in our society. Genetic causes of ID remain unknown because of its vast heterogeneity. Here we report two Finnish families and one Dutch family with affected individuals presenting with mild to moderate ID, neuropsychiatric symptoms and delayed speech development. By utilizing whole exome sequencing (WES), we identified a founder missense variant c.983T>C (p.Leu328Pro) in seven affected individuals from two Finnish consanguineous families and a deletion c.799_1034-429delinsTTATGA (p.Gln267fs) in one affected individual from a consanguineous Dutch family in the C12orf4 gene on chromosome 12. Both the variants co-segregated in the respective families as an autosomal recessive trait. Screening of the p.Leu328Pro variant showed enrichment in the North Eastern sub-isolate of Finland among anonymous local blood donors with a carrier frequency of 1:53, similar to other disease mutations with a founder effect in that region. To date, only one Arab family with a three affected individuals with a frameshift insertion variant in C12orf4 has been reported. In summary, we expand and establish the clinical and mutational spectrum of C12orf4 variants. Our findings implicate C12orf4 as a causative gene for autosomal recessive ID.

Investigating false start of the main growing season: A case of Uganda in East Africa.

False start of the growing season (Fsos) is a component of the onset variability related to agronomic drought that adversely impact on agricultural production and productivity. In the sub-Saharan Africa (SSA) where agriculture heavily depends on rainfall, the Fsos tends to create confusion among farmers on when to start planting crops thereby affecting seed germination and normal growth after emergence. In this paper, we focus on the Fsos and the occurrence of dry spell especially before the Start of growing Season (SoS). We take advantage of the existing rainfall estimates (CHIRPS) and remotely sensed data for vegetation performance (NDVI) over the period 1999-2017 in combination with local knowledge derived from farmers to map out areas at risk of (i) dry spell at the SoS, and (ii) false timing of SoS or high probability of occurrence of the Fsos. We found that the North Eastern part of Uganda (8.8% of arable area) were at risk of dry spell throughout each year. However, the greater North (58.1% of arable area) was prone to dry spell during the onset of the March-May season. Areas in the South Western (3.7%) region were at risk during the onset of the September-November season. The probability that a location in Uganda experiences an Fsos falls between 0-53%. The findings in this study are vital for planning of predictive adaptation to the impacts of climate variability on agriculture amid struggle aimed at tackling food insecurity challenge in the SSA.

De novo variants in CNOT3 cause a variable neurodevelopmental disorder.

As a result of exome-based sequencing work performed by the DDD study, de novo variants in CNOT3 have emerged as a newly recognised cause of a developmental disorder. This paper describes molecular and clinical details of 16 probands with developmental disorders and de novo CNOT3 variants. It is the first such description of the developmental phenotype associated with CNOT3 variants. Eight of these cases were discovered as part of the DDD study, while the other eight were found as a result of large-scale sequencing work performed by other groups. A highly specific phenotype was not recognised in these 16 cases. The most consistent phenotypic features seen in subjects with de novo variants in CNOT3 were hypotonia, relatively small stature, developmental delay, behavioural problems and intellectual disability. There is no easily recognisable facial phenotype, but some common dysmorphic features such as anteverted nares, thin upper lip and low set eyebrows were shared among some of the probands. Haploinsufficiency appears to be the most likely mechanism of action, with eight cases found to have protein-truncating variants. Of the other eight cases (all missense variants), three share an amino acid substitution at the same position which may therefore represent an important functional domain.

Smoking behaviour and knowledge of the health effects of smoking in patients with inflammatory bowel disease.

BACKGROUND: The detrimental effect of smoking on development and progression of Crohn's disease (CD) is generally accepted. AIM: To evaluate the awareness of smoking risks in a Belgian inflammatory bowel disease (IBD) population. METHODS: In the out-patient clinic of a tertiary referral centre, 625 consecutive patients with CD, 238 patients with ulcerative colitis (UC) and 289 non-IBD controls, filled out a simple questionnaire. This questionnaire included data on smoking behaviour and awareness of smoking-related health effects, including effects on IBD. RESULTS: At diagnosis, more CD patients were active smokers compared to UC (40% vs. 17%, P < 0.001). Remarkably, smoking cessation rates after diagnosis were similar for CD and UC (both 56%, P = 0.997). The great majority recognised a detrimental influence of smoking on general health (98-99%), lung cancer (95-97%), myocardial infarction (89-92%) and stroke (78-87%). Although CD patients more frequently acknowledged risks of smoking on their disease, only 37% were aware of a link with CD development, 30% of increased surgical rates and 27% of increased post-operative CD recurrence. Active smokers more frequently denied an increased risk of surgery and higher post-operative CD recurrence. Intriguingly, within the active smokers with CD, those not willing to quit smoking most often denied a potential bad influence of smoking. Taking into account disease duration, previous surgery, education level, working status and nicotine dependence, we were unable to define specific subgroups of patients requiring extra education. CONCLUSION: Although patients with Crohn's disease were better informed on the detrimental effects of smoking, the awareness rate was still low.

The duration of effect of infliximab maintenance treatment in paediatric Crohn's disease is limited.

BACKGROUND: Infliximab is effective for induction and maintenance of remission in children with moderately to severely active Crohn's disease (CD). AIM: To evaluate the long-term efficacy of infliximab treatment in paediatric CD. METHODS: In this observational, multicentre study, all paediatric CD patients in The Netherlands treated with infliximab from October 1992 to November 2009 and with minimal follow-up of 3 months since start of infliximab, were studied. RESULTS: One hundred and fifty-two CD patients [81M; median age at start of infliximab 15.0 years (IQR 13.1-16.4)] received a median number of 10.5 infliximab infusions (IQR 6-21). Median follow-up after start of infliximab was 25 months (IQR 13-40). Kaplan-Meier analysis showed that the cumulative probability of losing response to infliximab in patients who initially required repeated infusions was 13%, 40% and 50% after 1, 3 and 5 years, respectively. Seventy-four patients (49%) needed dose adjustments, with a median time to any adjustment of 6 months. CONCLUSIONS: Duration of effect of infliximab is limited as 50% of patients on infliximab maintenance treatment lose their therapeutic response after 5 years. Dose adjustments after start of infliximab are frequently needed to regain therapeutic benefit. These findings emphasise the need for effective, long-term treatment strategies for paediatric CD.