Detection of linkage to genes for quantitative traits remains a challenging task. Recently, variance components (VC) techniques have emerged as among the more powerful of available methods. As often implemented, such techniques require assumptions about the phenotypic distribution. Usually, multivariate normality is assumed. However, several factors may lead to markedly nonnormal phenotypic data, including (a) the presence of a major gene (not necessarily linked to the markers under study), (b) some types of gene x environment interaction, (c) use of a dichotomous phenotype (i.e., affected vs. unaffected), (d) nonnormality of the population within-genotype (residual) distribution, and (e) selective (extreme) sampling. Using simulation, we have investigated, for sib-pair studies, the robustness of the likelihood-ratio test for a VC quantitative-trait locus-detection procedure to violations of normality that are due to these factors. Results showed (a) that some types of nonnormality, such as leptokurtosis, produced type I error rates in excess of the nominal, or alpha, levels whereas others did not; and (b) that the degree of type I error-rate inflation appears to be directly related to the residual sibling correlation. Potential solutions to this problem are discussed. Investigators contemplating use of this VC procedure are encouraged to provide evidence that their trait data are normally distributed, to employ a procedure that allows for nonnormal data, or to consider implementation of permutation tests.

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.

Obesity is increasingly prevalent in the United States