Patterns of chromosomal evolution in Sigmodon, evidence from whole chromosome paints.

Of the superfamily Muroidea (31 genera, 1578 species), the Sigmodontinae (74 genera, 377 species) is the second largest subfamily in number of species and represents a significant radiation of rodent biodiversity. Only 2 of the 74 genera are found in both North and South America (Sigmodon and Oryzomys) and the remainder are exclusively from South America. In recent molecular studies, the genus Sigmodon (Cricetidae, Sigmodontinae) has been considered sister to many other South American Sigmodontines [Steppan et al., 2004]. We examine the chromosomal evolution of 9 species of Sigmodon utilizing chromosomal paints isolated from S. hispidus, proposed to be similar to the ancestral karyotype [Elder, 1980]. Utilizing a phylogenetic hypothesis of a molecular phylogeny of Sigmodon [Henson and Bradley, 2009], we mapped shared chromosomal rearrangements of taxa on a molecular tree to estimate the evolutionary position of each rearrangement. For several species (S. hirsutus, S. leucotis, S. ochrognathus, S. peruanus, and S. toltecus), the karyotype accumulated few or no changes, but in three species (S. arizonae, S. fulviventer, and S. mascotensis) numerous karyotype rearrangements were observed. These rearrangements involved heterochromatic additions, centric fusions, tandem fusions, pericentric inversions, as well as the addition of interstitial DNA not identified by chromosome paints or C-banding. The hypothesis that the ancestral karyotype for this complex had a diploid number of 52, a fundamental number of 52, and a G-band pattern of which most, if not all are similar to that present in modern day S. hispidus fails to be rejected. This hypothesis remains viable as an explanation of chromosomal evolution in Sigmodontine rodents.

Chromosomal evolution in tenrecs (Microgale and Oryzorictes, Tenrecidae) from the Central Highlands of Madagascar.

Tenrecs (Tenrecidae) are a widely diversified assemblage of small eutherian mammals that occur in Madagascar and Western and Central Africa. With the exception of a few early karyotypic descriptions based on conventional staining, nothing is known about the chromosomal evolution of this family. We present a detailed analysis of G-banded and molecularly defined chromosomes based on fluorescence in situ hybridization (FISH) that allows a comprehensive comparison between the karyotypes of 11 species of two closely related Malagasy genera, Microgale (10 species) and Oryzorictes (one species), of the subfamily Oryzorictinae. The karyotypes of Microgale taiva and M. parvula (2n = 32) were found to be identical to that of O. hova (2n = 32) most likely reflecting the ancestral karyotypes of both genera, as well as that of the Oryzorictinae. Parsimony analysis of chromosomal rearrangements that could have arisen following Whole Arm Reciprocal Translocations (WARTs) showed, however, that these are more likely to be the result of Robertsonian translocations. A single most parsimonious tree was obtained that provides strong support for three species associations within Microgale, all of which are consistent with previous molecular and morphological investigations. By expanding on a recently published molecular clock for the Tenrecidae we were able to place our findings in a temporal framework that shows strong chromosomal rate heterogeneity within the Oryzorictinae. We use these data to critically examine the possible role of chromosomal rearrangements in speciation within Microgale.

Chromosome painting among Proboscidea, Hyracoidea and Sirenia: support for Paenungulata (Afrotheria, Mammalia) but not Tethytheria.

Despite marked improvements in the interpretation of systematic relationships within Eutheria, particular nodes, including Paenungulata (Hyracoidea, Sirenia and Proboscidea), remain ambiguous. The combination of a rapid radiation, a deep divergence and an extensive morphological diversification has resulted in a limited phylogenetic signal confounding resolution within this clade both at the morphological and nucleotide levels. Cross-species chromosome painting was used to delineate regions of homology between Loxodonta africana (2n=56), Procavia capensis (2n=54), Trichechus manatus latirostris (2n=48) and an outgroup taxon, the aardvark (Orycteropus afer, 2n=20). Changes specific to each lineage were identified and although the presence of a minimum of 11 synapomorphies confirmed the monophyly of Paenungulata, no change characterizing intrapaenungulate relationships was evident. The reconstruction of an ancestral paenungulate karyotype and the estimation of rates of chromosomal evolution indicate a reduced rate of genomic repatterning following the paenungulate radiation. In comparison to data available for other mammalian taxa, the paenungulate rate of chromosomal evolution is slow to moderate. As a consequence, the absence of a chromosomal character uniting two paenungulates (at the level of resolution characterized in this study) may be due to a reduced rate of chromosomal change relative to the length of time separating successive divergence events.

Chromosomal evolution in the vlei rat, Otomys irroratus (Muridae: Otomyinae): a compound chromosomal rearrangement separates two major cytogenetic groups.

G- and C-banding delimits two cytogenetic groups within the vlei rat, Otomys irroratus. One has a diploid number of 2n = 24, resulting from a centric fusion of chromosomes 7 and 12 of the O. irroratus standard coupled with a tandem fusion to chromosome 8. The second has a diploid number of 2n = 28, lacks the compound chromosome, and appears to have a far wider geographic distribution within South Africa. Additionally, the two groups differ through the presence of cytotype-specific heterozygous centric fusions and one to three B chromosomes which appear as floating polymorphisms in the 2n = 28 complex.

Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis.

Leber congenital amaurosis (LCA, MIM 204000) accounts for at least 5% of all inherited retinal disease and is the most severe inherited retinopathy with the earliest age of onset. Individuals affected with LCA are diagnosed at birth or in the first few months of life with severely impaired vision or blindness, nystagmus and an abnormal or flat electroretinogram (ERG). Mutations in GUCY2D (ref. 3), RPE65 (ref. 4) and CRX (ref. 5) are known to cause LCA, but one study identified disease-causing GUCY2D mutations in only 8 of 15 families whose LCA locus maps to 17p13.1 (ref. 3), suggesting another LCA locus might be located on 17p13.1. Confirming this prediction, the LCA in one Pakistani family mapped to 17p13.1, between D17S849 and D17S960-a region that excludes GUCY2D. The LCA in this family has been designated LCA4 (ref. 6). We describe here a new photoreceptor/pineal-expressed gene, AIPL1 (encoding aryl-hydrocarbon interacting protein-like 1), that maps within the LCA4 candidate region and whose protein contains three tetratricopeptide (TPR) motifs, consistent with nuclear transport or chaperone activity. A homozygous nonsense mutation at codon 278 is present in all affected members of the original LCA4 family. AIPL1 mutations may cause approximately 20% of recessive LCA, as disease-causing mutations were identified in 3 of 14 LCA families not tested previously for linkage.

Insertional mutation of the collagen genes Col4a3 and Col4a4 in a mouse model of Alport syndrome.

Mice homozygous for the transgenic insertion in line OVE250 exhibit severe progressive glomerulonephritis. Ultrastructural changes in the glomerular basement membrane (GBM) at 2 weeks of age resemble those in Alport syndrome. The transgenic insertion site was mapped by FISH to mouse chromosome 1 close to Pax3. Genetic and molecular analyses identified a deletion of genomic DNA at the transgene insertion site. Exons 1 through 12 of the collagen IV gene Col4a4, exons 1 and 2 of the adjacent Col4a3 gene, and the intergenic promoter region are deleted. Transcripts of Col4a3 and Col4a4 are undetectable in mutant kidney, and both proteins are missing from the GBM. Persistent cellular proliferation in mutant kidneys suggests that interaction with the extracellular matrix may be important for cell maturation. Evolutionarily conserved sequence elements in the promoter regions of human and mouse Col4a3 and Col4a4 include a 19-bp element that was tandemly duplicated in the human lineage and a CTC box element common to several genes encoding extracellular matrix proteins. This new animal model of Alport syndrome, Col4Delta3-4, lacks both alpha3 and alpha4 chains of collagen IV and exhibits an earlier disease onset than mice lacking alpha3 only.

Expression of the rat liver carnitine palmitoyltransferase I (CPT-Ialpha) gene is regulated by Sp1 and nuclear factor Y: chromosomal localization and promoter characterization.

Carnitine palmitoyltransferase (CPT)-I catalyses the transfer of long-chain fatty acids from CoA to carnitine for translocation across the mitochondrial inner membrane. Expression of the 'liver' isoform of the CPT-I gene (CPT-Ialpha) is subject to developmental, hormonal and tissue-specific regulation. To understand the basis for control of CPT-Ialpha gene expression, we have characterized the proximal promoter of the CPT-Ialpha gene. Here, we report the sequence of 6839 base pairs of the promoter and the localization of the rat CPT-Ialpha gene to region q43 on chromosome 1. Our studies show that the first 200 base pairs of the promoter are sufficient to drive transcription of the CPT-Ialpha gene. Within this region are two sites that bind both Sp1 and Sp3 transcription factors. In addition, nuclear factor Y (NF-Y) binds the proximal promoter. Mutation at the Sp1 or NF-Y sites severely decreases transcription from the CPT-Ialpha promoter. Other protein binding sites were identified within the first 200 base pairs of the promoter by DNase I footprinting, and these elements contribute to CPT-Ialpha gene expression. Our studies demonstrate that CPT-Ialpha is a TATA-less gene which utilizes NF-Y and Sp proteins to drive basal expression.

YAC rescue of downless locus mutations in mice.

Mice with mutations at the downless (dl) locus have defects in hair follicle, tooth, sweat gland, preputial gland, Meibomian gland, and tail development. The dl phenotype is analogous to the human genetic disorder termed autosomal hypohidrotic (or anhidrotic) ectodermal dysplasia (HED). On the basis of the identification of two related transgenic insertional mutations in the downless gene, yeast artificial chromosomes (YACs) were identified that map to the critical region of mouse Chromosome (Chr) 10. To determine which of the YACs contain the dl gene, we generated YAC transgenic mice by mouse embryo microinjections. The 200-kb YAC B25.D9 was found to rescue all of the downless defects. In addition, the transgenic YAC rescued the dominant Sleek (Dlslk) allele. Since the sequences within the YAC are entirely deleted in one of the transgenic mutants, our results establish that Sleek encodes a dominant-negative protein whose effects can be reversed by expression of extra copies of the wild-type locus.

Inversin, a novel gene in the vertebrate left-right axis pathway, is partially deleted in the inv mouse.

Visceral left-right asymmetry occurs in all vertebrates, but the inversion of embryo turning (inv) mouse, which resulted following a random transgene insertion, is the only model in which these asymmetries are consistently reversed. We report positional cloning of the gene underlying this recessive phenotype. Although transgene insertion was accompanied by neighbouring deletion and duplication events, our YAC phenotype rescue studies indicate that the mutant phenotype results from the deletion. After extensively characterizing the 47-kb deleted region and flanking sequences from the wild-type mouse genome, we found evidence for only one gene sequence in the deleted region. We determined the full-length 5.5-kb cDNA sequence and identified 16 exons, of which exons 3-11 were eliminated by the deletion, causing a frameshift. The novel gene specifies a 1062-aa product with tandem ankyrin-like repeat sequences. Characterization of complementing and non-complementing YAC transgenic families revealed that correction of the inv mutant phenotype was concordant with integration and intact expression of this novel gene, which we have named inversin (Invs).

A molecular cytogenetic analysis of X chromosome repatterning in the Bovidae: transpositions, inversions, and phylogenetic inference.

Chromosomal homologies among the X chromosomes of species representative of eight bovid subfamilies and most of the recognized tribes were established using a combination of FISH and conventional G- and C-banding. Our analyses allowed for the delimitation of three X chromosome types represented, respectively, by cattle (Bovinae, tribe Bovini), the tragelaphines (Bovinae, tribe Tragelaphini), and a large assemblage comprising all the remaining subfamilies and their tribes (the Cephalophinae, Hippotraginae, Alcelaphinae, Antilopinae, Aepycerotinae, Peleinae, and Caprinae). The use of the bacterial artificial chromosome probe BAC 101 (which maps to Xp12 in cattle) and an Xp painting probe comprising sequences specific for the short arm of cattle Xp (Xp24-->p12) allowed us to orient this region, which has moved as a conserved euchromatic block during the evolution of the bovid X chromosome. We show that the differences between the three chromosomal types are attributable to a transposition, two inversions, and heterochromatic additions/deletions. A paucity of comparative mapping data precludes the assignment of the sequences contained in cattle Xp to either the presumed conserved (XCR) or the recently added (XAR) region of the eutherian X chromosome, and the reasons for the retention of these sequences as an evolutionarily conserved unit in the intrachromosomal restructuring of the bovid X across lineages remain enigmatic.

Genomic DNA sequence, promoter expression, and chromosomal mapping of rat muscle carnitine palmitoyltransferase I.

Carnitine palmitoyltransferase I (CPT-I) is a key enzyme involved in the regulation of fatty acid oxidation. CPT-IA and CPT-IB are isoforms of carnitine palmitoyltransferase I, of which CPT-IA is expressed in liver, kidney, fibroblasts, and heart and CPT-IB is expressed in skeletal muscle, heart, brown and white adipocytes, and testes. Although the genomic DNA sequence of human CPT-IB is available, the transcription start site and upstream regulatory sequences are not known. For rat CPT-IB, only the cDNA sequence has been published. We have cloned the entire rat CPT-IB gene from a Lambda fix II rat kidney genomic library. The genomic structure contains 19 exons, with the transcription start site for CPT-IB located in a short first exon, which is a 13-bp extension to the previously published cDNA 5' sequence. The coding sequence is identical with the rat muscle cDNA. The rat CPT-IB gene contains 18 introns and 19 exons, the latter 18 exons showing 85% homology to the human CPT-IB cDNA. CPT-IB maps to rat chromosome 7 at band q34. A putative promoter region was identified to within 391 bp of the transcription start site. The muscle specificity of the 5' flanking region was verified by comparison of luciferase expression to that of beta-galactosidase in cardiac myocytes and in HepG2 cells.

Chromosome 1p36 deletions: the clinical phenotype and molecular characterization of a common newly delineated syndrome.

Deletions of the distal short arm of chromosome 1 (1p36) represent a common, newly delineated deletion syndrome, characterized by moderate to severe psychomotor retardation, seizures, growth delay, and dysmorphic features. Previous cytogenetic underascertainment of this chromosomal deletion has made it difficult to characterize the clinical and molecular aspects of the syndrome. Recent advances in cytogenetic technology, particularly FISH, have greatly improved the ability to identify 1p36 deletions and have allowed a clearer definition of the clinical phenotype and molecular characteristics of this syndrome. We have identified 14 patients with chromosome 1p36 deletions and have assessed the frequency of each phenotypic feature and clinical manifestation in the 13 patients with pure 1p36 deletions. The physical extent and parental origin of each deletion were determined by use of FISH probes on cytogenetic preparations and by analysis of polymorphic DNA markers in the patients and their available parents. Clinical examinations revealed that the most common features and medical problems in patients with this deletion syndrome include large anterior fontanelle (100%), motor delay/hypotonia (92%), moderate to severe mental retardation (92%), growth delay (85%), pointed chin (80%), eye/vision problems (75%), seizures (72%), flat nasal bridge (65%), clinodactyly and/or short fifth finger(s) (64%), low-set ear(s) (59%), ear asymmetry (57%), hearing deficits (56%), abusive behavior (56%), thickened ear helices (53%), and deep-set eyes (50%). FISH and DNA polymorphism analysis showed that there is no uniform region of deletion but, rather, a spectrum of different deletion sizes with a common minimal region of deletion overlap.

Human glutamate pyruvate transaminase (GPT): localization to 8q24.3, cDNA and genomic sequences, and polymorphic sites.

Two frequent protein variants of glutamate pyruvate transminase (GPT) (E.C.2.6.1.2) have been used as genetic markers in humans for more than two decades, although chromosomal mapping of the GPT locus in the 1980s produced conflicting results. To resolve this conflict and develop useful DNA markers for this gene, we isolated and characterized cDNA and genomic clones of GPT. We have definitively mapped human GPT to the terminus of 8q using several methods. First, two cosmids shown to contain the GPT sequence were derived from a chromosome 8-specific library. Second, by fluorescence in situ hybridization, we mapped the cosmid containing the human GPT gene to chromosome band 8q24.3. Third, we mapped the rat gpt cDNA to the syntenic region of rat chromosome 7. Finally, PCR primers specific to human GPT amplify sequences contained within a "half-YAC" from the long arm of chromosome 8, that is, a YAC containing the 8q telomere. The human GPT genomic sequence spans 2,7 kb and consists of 11 exons, ranging in size from 79 to 243 bp. The exonic sequence encodes a protein of 495 amino acids that is nearly identical to the previously reported protein sequence of human GPT-1. The two polymorphic GPT isozymes are the results of a nucleotide substitution in codon 14, coding for a histidine in GPT-1 and an asparagine in GPT-2, which causes a gain or loss of an NlaIII restriction site. In addition, a cosmid containing the GPT sequence also contains a previously unmapped, polymorphic microsatellite sequence, D8S421. The cloned GPT gene and associated polymorphisms will be useful for linkage and physical mapping of disease loci that map to the terminus of 8q, including atypical vitelliform macular dystrophy (VMD1) and epidermolysis bullosa simplex, type Ogna (EBS1). In addition, this will be a useful system for characterizing the telomeric region of 8q. Finally, determination of the molecular basis of the GPT isozyme variants will permit PCR-based detection of this world-wide polymorphism.

X chromosome evolution in the suni and eland antelope: detection of homologous regions by fluorescence in situ hybridization and G-banding.

Comparative cytogenetics and fluorescence in situ hybridization (FISH) were used to track structural rearrangements in the X chromosomes of two African antelope species, the eland (Taurotragus oryx; tribe Tragelaphini) and the suni (Neotragus moschatus; tribe Neotragini). Using two microdissected cattle chromosome painting probes (one specific for Xp-containing sequences corresponding to Xp24-->p12 of the cattle X, and one specific for Xq-containing sequences corresponding to Xq12-->qter), we show that intrachromosomal rearrangements distinguish the X chromosomes of these species. Furthermore, there is clear evidence that, superimposed on this background of intrachromosomal evolutionary change, the sequences contained in the cattle Xp painting probe appear to have moved as a complete unit during the repatterning of the bovid X. Although we are unable to infer the order of the rearranged chromosomal segments, given the large regions of homology detected by the chromosome paints, we nonetheless believe that this approach (combining conventional and molecular cytogenetic studies on the X chromosome) will prove useful for inferring phylogenetic relationships in the family Bovidae, particularly as more probes become available.

Chromosomes of Brants' whistling rat and genome conservation in the Otomyinae revealed by G-banding and fluorescence in situ hybridization.

Conventional G- and C-banding were used to describe the chromosomes of the whistling rat, Parotomys brantsii. This species has a diploid number of 42 chromosomes. C-banding showed that large blocks of pericentromeric heterochromatin or entirely heterochromatic short arms characterize most chromosomes. G-banding and fluorescence in situ hybridization (FISH) incorporating two laboratory mouse chromosome paints were used to compare the genomes of P. brantsii, the bush karoo rat (Otomys unisulcatus; 2n = 28), and the vlei rat (O. irroratus; 2n = 28-31). The FISH results showed that sequences corresponding to mouse chromosome 2 are conserved as a single chromosome in O. irroratus but are found on two separate chromosomes in P. brantsii and O. unisulcatus. In contrast, a mouse chromosome 6 paint showed hybridization to single chromosomes in all three species examined. When taken together, the FISH and cytogenetic results produce two important findings: (1) previously undetected homoeologies between the two Otomys species can be identified and (2) a high proportion of conserved chromosomes exists between P. brantsii and O. unisulcatus. This, in conjunction with previously reported allozyme and immunoblot data, raises serious questions about the validity of the current generic taxonomy of the Otomyinae.

Characterization of human DSPG3, a small dermatan sulfate proteoglycan.

PG-Lb is a small dermatan sulfate proteoglycan that has been previously characterized in chicken. In the developing limb, chick PG-Lb appears to be exclusively expressed in the zone of flattened chondrocytes. We have cloned and sequenced the human homolog to chick PG-Lb from two human chondrocyte cDNA libraries and a human chondrocyte RNA sample. The human homolog has been named DSPG3, as it is the third member of the small dermatan sulfate proteoglycan family to be identified and characterized along with biglycan (PG-I) and decorin (PG-II). DSPG3 maps to chromosome 12q21 and is composed of 1515 nucleotides of cDNA that code for a 322-amino-acid protein. The protein contains three potential glycosaminoglycan attachment sites, two N-glycosylation sites, a poly- glutamic acid stretch, and six cysteines. By Northern analysis, we have demonstrated that DSPG3 is expressed in cartilage, as well as ligament and placental tissues.

Brachmann-de Lange syndrome: autosomal dominant inheritance and male-to-male transmission.

We report on familial occurrence of the Brachmann-de Lange syndrome (BDLS): a mildly affected father and his severely affected son and daughter who have different mothers. Both children are severely affected while the father has a much milder but definite BDLS phenotype. Our report documents the third example of male-to-male transmission and adds to the argument against exclusively maternal transmission in familial cases. In addition, our findings illustrate the occurrence of severe manifestations in cases of familial BDLS.

Prenatal diagnosis of uniparental disomy 15 following trisomy 15 mosaicism.

Maternal uniparental disomy 15 (UPD15), responsible for approximately 25 per cent of Prader-Willi syndrome cases, is usually caused by maternal meiosis I non-disjunction associated with advanced maternal age. These cases may initially be detected as mosaic trisomy 15 during routine prenatal diagnostic studies. In such cases, PCR (polymerase chain reaction) microsatellite analysis of uncultured cells makes prospective prenatal diagnosis for UPD15 possible with results available in 2-4 days. We have performed molecular analyses on a series of seven cases of mosaic trisomy 15 identified in amniotic fluid (AF, n = 3) or chorionic villus samples (CVS, n = 4) from patients initially referred for advanced maternal age or abnormal triple screen. In all cases, the maternal ages were > or = 35 years and maternal meiosis I non-disjunction was documented as the cause of the trisomy in all informative cases (n = 5). Of the three case with mosaic trisomy 15 at amniocentesis, two showed the presence of the trisomy in the fetus. Molecular analysis showed one case with maternal UPD15 in the euploid cell line and one case with biparental inheritance. Both of these families elected to terminate the pregnancies based on the presence of true fetal mosaicism. In the third case, low-level trisomy 15 mosaicism in the amniotic fluid was not confirmed in a follow-up amniotic fluid sample and molecular analysis indicated biparental inheritance in the fetus. For the four trisomy 15 mosaics detected at CVS, molecular analysis was performed on direct amniotic fluid cell lysates for prospective diagnosis of UPD at 14-16 weeks' gestation. Follow-up cytogenetic analysis of the amniotic fluid in all four cases was normal, indicating confined placental mosaicism. Molecular analysis showed one of these four cases to have maternal heterodisomy 15. Based on the likelihood of Prader-Willi syndrome due to maternal UPD15, the couple chose to terminate the pregnancy. The total of two of seven cases of trisomy 15 mosaicism resulting in UPD15 is consistent with the theoretical expectation of one-third and indicates a high risk of UPD in such pregnancies. Therefore, UPD testing should be offered in all cases of mosaic trisomy 15 encountered in CVS or amniocentesis.

Chromosomal evolution in duiker antelope (Cephalophinae: Bovidae): karyotype comparisons, fluorescence in situ hybridization, and rampant X chromosome variation.

Fluorescence in situ hybridization (FISH) and conventional banding techniques were used to identify patterns of similarity among the genomes of six species of antelope, subfamily Cephalophinae. The G-banded euchromatic portions of the autosomes were invariable in all species; however, significant modifications of the X chromosomes were detected. Two of the taxa, Cephalophus maxwellii and C. monticola, were characterized by acrocentric X's, while X chromosome morphology varied from submetacentric to metacentric in the remaining species (C. dorsalis, C. natalensis, Sylvicapra grimmia, and C. silvicultor). The short arm of the X was heterochromatic in each species. Total genomic DNAs from these antelope were used as hybridization probes against Cephalophus metaphase chromosomes and resulted in robust fluorescence in the pericentromeric region of each autosome and in the heterochromatic short arm of the X chromosome, indicating complimentarity of DNA sequences in these regions. Conversely, chromosome painting involving genomic DNAs derived from the subfamilies Alcelaphinae (Pygargus dorcas) and Neotraginae (Oreotragus oreotragus) showed a marked absence of hybridization at these sites. Additionally, X chromosome comparisons between the Cephalophinae and Bovinae (represented by Bos taurus) revealed two euchromatic pericentric inversions which had occurred since their common ancestry. There is good G-band homoeology between the inverted cattle chromosome region Xq12 --> q34 and most of the proximal portion of Xq in duikers, as well as between the distal third of the duiker Xq and the cattle Xp. The latter rearrangement was further confirmed by in situ hybridization using a probe containing an insert spanning bands p12 to p14 of the cattle X chromosome.

Leukocyte adhesion deficiency mimicking Hirschsprung disease.

An infant had clinical signs suggestive of Hirschsprung disease as the initial manifestation of leukocyte adhesion deficiency. Chromosome studies showed a deletion of the distal third of the long arm of one chromosome 21, and flow cytometric studies confirmed the defective expression of CD18.