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V A McKusick

Publications and source records attributed to V A McKusick.

At least 19 recordsLinked to original sources
PubMed2001

The sequence of the human genome.

A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies-a whole-genome assembly and a regional chromosome assembly-were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional approximately 12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.

Algorithms↗
PubMed2001

Implications of the Human Genome Project for medical science.

The year 2000 marked both the start of the new millennium and the announcement that the vast majority of the human genome had been sequenced. Much work remains to understand how this "instruction book for human biology" carries out its multitudes of functions. But the consequences for the practice of medicine are likely to be profound. Genetic prediction of individual risks of disease and responsiveness to drugs will reach the medical mainstream in the next decade or so. The development of designer drugs, based on a genomic approach to targeting molecular pathways that are disrupted in disease, will follow soon after. Potential misuses of genetic information, such as discrimination in obtaining health insurance and in the workplace, will need to be dealt with swiftly and effectively. Genomic medicine holds the ultimate promise of revolutionizing the diagnosis and treatment of many illnesses.

Human Genome Project↗
PubMed2000

Online Mendelian Inheritance in Man (OMIM).

Online Mendelian Inheritance In Man (OMIM) is a public database of bibliographic information about human genes and genetic disorders. Begun by Dr. Victor McKusick as the authoritative reference Mendelian Inheritance in Man, it is now distributed electronically by the National Center for Biotechnology Information (NCBI). Material in OMIM is derived from the biomedical literature and is written by Dr. McKusick and his colleagues at Johns Hopkins University and elsewhere. Each OMIM entry has a full text summary of a genetic phenotype and/or gene and has copious links to other genetic resources such as DNA and protein sequence, PubMed references, mutation databases, approved gene nomenclature, and more. In addition, NCBI's neighboring feature allows users to identify related articles from PubMed selected on the basis of key words in the OMIM entry. Through its many features, OMIM is increasingly becoming a major gateway for clinicians, students, and basic researchers to the ever-growing literature and resources of human genetics.

Alleles↗
PubMed2000

Overlap of PIV syndrome, VACTERL and Pallister-Hall syndrome: clinical and molecular analysis.

The polydactyly, imperforate anus, vertebral anomalies syndrome (PIV, OMIM 174100) was determined as a distinct syndrome by Say and Gerald in 1968 (Say B, Gerald PS. Lancet 1968: 2: 688). We noted that the features of PIV overlap with the VATER association and Pallister-Hall syndrome (PHS, OMIM 146510), which includes polydactyly, (central or postaxial), shortened fingers, hypoplastic nails, renal anomalies, imperforate anus, and hypothalamic hamartoma. Truncation mutations in GL13, a zinc finger transcription factor gene, have been shown to cause PHS. We performed a molecular evaluation on a patient diagnosed with PIV, whose mother, grandfather, and maternal aunt had similar malformations. We sequenced the GLI3 gene in the patient to determine if she had a mutation. The patient was found to have a deletion in nucleotides 2188-2207 causing a frameshift mutation that predicts a truncated protein product of the gene. Later clinical studies demonstrated that the patient also has a hypothalamic hamartoma, a finding in PHS. We concluded that this family had atypical PHS and not PIV. This result has prompted us to re-evaluate the PIV literature to see if PIV is a valid entity. Based on these data and our examination of the literature, we conclude that PIV is not a valid diagnostic entity. We conclude that patients diagnosed with PIV should be reclassified as having VACTERL, or PHS, or another syndrome with overlapping malformations.

Abnormalities, Multiple↗
PubMed1999

Small deletions in the type II collagen triple helix produce kniest dysplasia.

Kniest dysplasia is a moderately severe type II collagenopathy, characterized by short trunk and limbs, kyphoscoliosis, midface hypoplasia, severe myopia, and hearing loss. Mutations in the gene that encodes type II collagen (COL2A1), the predominant protein of cartilage, have been identified in a number of individuals with Kniest dysplasia. All but two of these previously described mutations cause in-frame deletions in type II collagen, either by small deletions in the gene or splice site alterations. Furthermore, all but one of these mutations is located between exons 12 and 24 in the COL2A1 gene. We used heteroduplex analysis to identify sequence anomalies in five individuals with Kniest dysplasia. Sequencing of the index patients' genomic DNA identified four new dominant mutations in COL2A1 that result in Kniest dysplasia: a 21-bp deletion in exon 16, an 18-bp deletion in exon 19, and 4-bp deletions in the splice donor sites of introns 14 and 20. A previously described 28-bp deletion at the COL2A1 exon 12-intron 12 junction, deleting the splice donor site, was identified in the fifth case. The latter three mutations are predicted to result in exon skipping in the mRNA encoded from the mutant allele. These data suggest that Kniest dysplasia results from shorter type II collagen monomers, and support the hypothesis that alteration of a specific COL2A1 domain, which may span from exons 12 to 24, leads to the Kniest dysplasia phenotype.

Base Sequence↗
PubMed1999

Cloning of multiple keratin 16 genes facilitates prenatal diagnosis of pachyonychia congenita type 1.

Pachyonychia congenita type 1 (PC-1) is an autosomal dominant ectodermal dysplasia characterized by severe nail dystrophy, focal non-epidermolytic palmoplantar keratoderma (FNEPPK) and oral lesions. We have previously shown that mutations in keratin K16 cause fragility of specific epithelia resulting in phenotypes of PC-1 or FNEPPK alone. These earlier analyses employed an RT-PCR approach to avoid amplification of K16-like pseudogenes. Here, we have cloned the K16 gene (KRT16A) and two homologous pseudogenes (psiKRT16B and psiKRT16C), allowing development of a genomic mutation detection strategy based on a long-range PCR, which is specific for the functional K16 gene. We report a novel heterozygous 3 bp deletion mutation (388del3) in K16 in a sporadic case of PC-1. The mutation was detected in genomic DNA and confirmed at the mRNA level by RT-PCR, showing that our genomic PCR system is reliable for K16 mutation detection. Using this system, we carried out the first prenatal diagnosis for PC-1 using CVS material, correctly predicting a normal fetus. This work will greatly improve K16 mutation analysis and allow predictive testing for PC-1 and the related phenotype of FNEPPK.

Abnormalities, Multiple↗
PubMed1997

Deletion of PTEN in a patient with Bannayan-Riley-Ruvalcaba syndrome suggests allelism with Cowden disease.

We report on an 18-month-old boy with an interstitial deletion at 10q23.2-q24.1. This region includes the PTEN gene, mutations of which have been reported to cause Cowden disease. Our patient presented with manifestations of Bannayan-Riley-Ruvalcaba (BRR) syndrome. The BRR syndrome is a rare disorder which presents most commonly in childhood. Cowden disease is a disease of adulthood and is inadequately described in children. Because of the considerable phenotypic overlap between the two disorders, and the cytogenetic and molecular findings in our patient, we suggest that BRR syndrome and Cowden disease are allelic.

Adult↗