Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B.

Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B. Corpus callosum abnormalities are common brain malformations with a wide clinical spectrum ranging from severe intellectual disability to normal cognitive function. The etiology is expected to be genetic in as much as 30-50% of the cases, but the underlying genetic cause remains unknown in the majority of cases. By next-generation mate-pair sequencing we mapped the chromosomal breakpoints of a patient with a de novo balanced translocation, t(1;6)(p31;q25), agenesis of corpus callosum (CC), intellectual disability, severe speech impairment, and autism. The chromosome 6 breakpoint truncated ARID1B which was also truncated in a recently published translocation patient with a similar phenotype. Quantitative polymerase chain reaction (Q-PCR) data showed that a primer set proximal to the translocation showed increased expression of ARID1B, whereas primer sets spanning or distal to the translocation showed decreased expression in the patient relative to a non-related control set. Phenotype-genotype comparison of the translocation patient to seven unpublished patients with various sized deletions encompassing ARID1B confirms that haploinsufficiency of ARID1B is associated with CC abnormalities, intellectual disability, severe speech impairment, and autism. Our findings emphasize that ARID1B is important in human brain development and function in general, and in the development of CC and in speech development in particular.

4q35 deletion and 10p15 duplication associated with immunodeficiency.

We report a familial cryptic reciprocal translocation between 4q35 and 10p15 leading to deletion of the terminal long arm of chromosome 4 and duplication of the terminal short arm of chromosome 10 in two family members who both have immunological disturbances and a similar facial appearance. The precise location and extent of the deletion and duplication was determined by fluorescence in situ hybridization (FISH). Furthermore, we investigated the deletion breakpoint of a previously reported patient with 4q34.3-qter deletion [Van Buggenhout et al. (2004); Am J Med Genet Part A 131A:186-189].

No association between birth weight and Type 1 diabetes mellitus--a twin-control study.

AIMS: To investigate, by means of a twin-control study, whether there is a relationship between birth weight and Type 1 diabetes mellitus. METHODS: In the youngest part (n = 20 888 pairs) of the Danish Twin Register, 95 twin pairs (26 monozygotic and 69 dizygotic) with Type 1 diabetes were identified. Information about birth weight and birth length, prematurity, maternal age and parity was obtained from midwives' records and from the Danish Medical Birth Registry and analysed using Student's two-sided t-test, Chi-square test and logistic regression. RESULTS: Birth data were available for 83 diabetic and 51 healthy twin individuals, altogether 67 twin pairs (20 monozygotic and 47 dizygotic). Mean birth weight was 2537 g and 2565 g (NS) in monozygotic and dizygotic pairs and the corresponding length at birth 47.6 cm and 48.2 cm (NS). In pairs discordant for diabetes, the mean birth weight was 2538 g in twins with diabetes and 2549 g in twins without diabetes (NS). Logistic regression in discordant pairs showed no relationship between diabetes status and birth weight, birth length, birth order, sex or prematurity. Logistic regression in concordant vs. discordant pairs showed no effect of mean birth weight and birth length, maternal age, parity or weeks of prematurity. CONCLUSIONS: There is no association between Type 1 diabetes mellitus and birth weight in this study. Furthermore, variables related to birth weight and length cannot explain why some pairs are concordant while other remain discordant.

Previous maternal abortion, longer gestation, and younger maternal age decrease the risk of type 1 diabetes among male offspring.

OBJECTIVE: To identify possible influences and interactions of perinatal determinants in the subsequent development of type 1 diabetes. RESEARCH DESIGN AND METHODS: The data were obtained from children born in Denmark during the periods 1978-1982 and 1984-1986 and admitted to a Danish hospital with newly diagnosed type 1 diabetes between 1978 and 1995; 857 patients fulfilled the criteria. The study was conducted by combining and analyzing two national registries: the National Patient Registry and the Medical Birth Registry. For each diabetic child, two control children were randomly selected, matched by sex, time, and district of delivery. RESULTS: By multivariate logistic regression analysis, the following significant determinants were identified. Male offspring showed decreased risk when born of mothers who had had one or more abortions (odds ratio [OR] 0.66 [95% CI 0.48-0.92]) and with long duration of gestation (linearly with OR 0.91 per week [0.85-0.99]), while increased risk was found for high maternal age (linearly with OR 1.03 per year [1.00-1.06]). Female offspring showed no such association. No significant differences between diabetic patients and control subjects were found with respect to paternal age, maternal parity, placental weight or any of the birth size parameters, or interventions and complications during delivery. CONCLUSIONS: The findings show that perinatal determinants may influence the risk of subsequent development of type 1 diabetes in a sex-specific manner.

Failure of high-dose insulin treatment to increase beta-cell insulin content in diabetic non obese diabetic (NOD) mice.

High-dose insulin treatment in the first period after clinical onset of insulin-dependent diabetes mellitus (IDDM) has been found to reduce diabetic manifestations in humans. The aim of the present study was to examine whether high-dose insulin treatment of newly diagnosed diabetic non obese diabetic (NOD) mice would increase beta-cell insulin content after termination of treatment in this experimental IDDM animal model. Newly diagnosed diabetic female NOD mice were randomized into three groups composed of a low-dose insulin treated group (n = 10) injected subcutaneously with 15 IU/kg per day of NPH for 14 days followed by 5 days without insulin, a high-dose insulin treated group (n = 8) injected subcutaneously with 150 IU/kg per day of Actrapid for 14 days followed by 5 days without insulin and an untreated group sacrificed 3 days after diagnosis (n = 11). A reference group of age matched non-diabetic untreated female NOD mice (n = 11) was included in the study and sacrificed at the same time as the untreated diabetic mice. No significant difference in the amount of insulin extracted from the total pancreas was found by comparison of the three diabetic groups, consisting of the newly diagnosed untreated mice, the low-dose insulin treated mice and the high-dose insulin treated mice, respectively. The level was about 100-fold less than in the non-diabetic group. Blood glucose values in the two treated diabetic groups were at a high level (median > 18 mM) throughout the study. We conclude that no increase in beta-cell insulin content could be demonstrated in newly diagnosed diabetic NOD mice after early high-dose insulin treatment, at least not in the presence of high blood glucose values.