Correction: Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability.

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Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families.

Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations (ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7 and USP44), and missense mutations include the first reports of variants in BDNF or TET1 associated with ID. The genes identified also showed overlap with de novo gene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.

Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability.

Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1-3% of the general population. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause autosomal recessive ID (ARID) has lagged behind, predominantly due to non-availability of sizeable families. Here we present the results of exome sequencing in 121 large consanguineous Pakistani ID families. In 60 families, we identified homozygous or compound heterozygous DNA variants in a single gene, 30 affecting reported ID genes and 30 affecting novel candidate ID genes. Potential pathogenicity of these alleles was supported by co-segregation with the phenotype, low frequency in control populations and the application of stringent bioinformatics analyses. In another eight families segregation of multiple pathogenic variants was observed, affecting 19 genes that were either known or are novel candidates for ID. Transcriptome profiles of normal human brain tissues showed that the novel candidate ID genes formed a network significantly enriched for transcriptional co-expression (P<0.0001) in the frontal cortex during fetal development and in the temporal-parietal and sub-cortex during infancy through adulthood. In addition, proteins encoded by 12 novel ID genes directly interact with previously reported ID proteins in six known pathways essential for cognitive function (P<0.0001). These results suggest that disruptions of temporal parietal and sub-cortical neurogenesis during infancy are critical to the pathophysiology of ID. These findings further expand the existing repertoire of genes involved in ARID, and provide new insights into the molecular mechanisms and the transcriptome map of ID.

Are patients at Veterans Affairs medical centers sicker? A comparative analysis of health status and medical resource use.

BACKGROUND: The Veterans Affairs (VA) health system has been criticized for being inefficient based on comparisons of VA care with non-VA care. Whether such comparisons are biased by differences between the VA patient population and the non-VA patient population is not known. Our objective is to determine if VA patients are different from non-VA patients in terms of health status and medical resource use. METHOD: We analyzed 128,099 records from the National Health Interview Survey for the years 1993 and 1994. We compared the VA patient population with the general patient population for self report on health status, number of medical conditions, number of outpatient physician visits, number of hospital admissions, and number of hospital days each year. RESULTS: The VA patient population had poorer health status (odds ratio [OR], 14.7; 95% confidence interval [CI], 10.7-20.2), more medical conditions (OR, 14; 95% CI, 10.5-18.7), and higher medical resource use compared with the general patient population (OR, 3.7 for 3 or more physician visits per year; OR 5.4 for 3 or more hospital admissions per year; OR, 7.7 for 21 or more days spent in a hospital per year). However, after controlling for health and sociodemographic differences, VA patients had similar resource use compared with the general patient population. CONCLUSION: Large differences in sociodemographic status, health status, and subsequent resource use exist between the VA and the general patient population. Therefore, comparisons of VA care with non-VA care need to take these differences into account. Furthermore, health care planning and resource allocation within the VA should not be based on data extrapolated from non-VA patient populations. Arch Intern Med. 2000;160:3252-3257.

Cost minimization analysis of telepathology.

Telepathology is gaining acceptance as a mode of providing pathology services to remote sites, but its economic feasibility is unknown. A dynamic robotic telepathology service between the Veterans Affairs Medical Center, Iron Mountain, MI, and the Veterans Affairs Medical Center, Milwaukee, WI, provides diagnostic services for routine and frozen section surgical pathology cases at Iron Mountain. We conducted a cost minimization analysis of this service by building a model to compare telepathology and on-site pathology in Iron Mountain and a courier method of transporting specimens from Iron Mountain to Milwaukee for diagnosis. Base case analysis showed the courier method to be the most economic; telepathology was less costly than on-site pathology. If the costs of telepathology equipment and telecommunication are lowered to reflect current cost, then telepathology becomes the favored option. Telepathology can be an economic mode of providing pathology services to a remote site.