A dual-color FISH assay distinguishes between ELL and MLLT1 (ENL) gene rearrangements in t(11;19)-positive acute leukemia.
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Acute Disease↗
Biomedical subjects
L G Shaffer
Publications and source records attributed to L G Shaffer.
Rearrangements of chromosome 18 illustrate the utility of array-based comparative genomic hybridization.
Comprehensive and reliable testing is an important component of counseling and management in clinical genetics. Identification of imbalances of chromosomal segments has uncovered new genes and has established phenotype/genotype correlations for many syndromes with previously unidentified causes. Conventional cytogenetics has proven to be useful for the detection of large aberrations, but its resolution limits the identification of submicroscopic alterations. Comparative genomic hybridization (CGH) on a microarray-based platform has the potential to detect and characterize both microscopic and submicroscopic chromosomal abnormalities. Nine cases of aberrations involving chromosome 18 are used to illustrate the use and clinical potential of array CGH.
Child↗
Medical applications of array CGH and the transformation of clinical cytogenetics.
Microarray-based comparative genomic hybridization (array CGH) merges molecular diagnostics with traditional chromosome analysis and is transforming the field of cytogenetics. Prospective studies of individuals with developmental delay and dysmorphic features have demonstrated that array CGH has the ability to detect any genomic imbalance including deletions, duplications, aneuploidies and amplifications. Detection rates for chromosome abnormalities with array CGH range from 5-17% in individuals with normal results from prior routine cytogenetic testing. In addition, copy number variants (CNVs) were identified in all studies. These CNVs may include large-scale variation and can confound the diagnostic interpretations. Although cytogeneticists will require additional training and laboratories must become appropriately equipped, array CGH holds the promise of being the initial diagnostic tool in the identification of visible and submicroscopic chromosome abnormalities in mental retardation and other developmental disabilities.
Chromosome Aberrations↗
Partial trisomy of chromosome 10(q22-q24) due to maternal insertional translocation (15;10).
Interchromosomal insertional translocations are rare chromosome rearrangements with an incidence of about 1:80,000 live births. We report on the clinical and cytogenetic findings of a newborn baby with partial trisomy 10q22-10q24 due to a maternal insertional translocation 15;10. Partial trisomy of the long arm of chromosome 10 is a distinctive chromosome aberration characterized by prenatal-onset growth retardation and craniofacial, skeletal, and other somatic anomalies. Most cases are unbalanced products from reciprocal chromosome translocations, and insertional translocations are rarely involved. The proband was initially referred because of severe intrauterine growth retardation, and fluorescence in situ hybridization (FISH) using painting probes confirmed the maternal balanced (15;10) insertion.
Abnormalities, Multiple↗
Epigenetic detection of human chromosome 14 uniparental disomy.
The recent demonstration of genomic imprinting of DLK1 and MEG3 on human chromosome 14q32 indicates that these genes might contribute to the discordant phenotypes associated with uniparental disomy (UPD) of chromosome 14. Regulation of imprinted expression of DLK1 and MEG3 involves a differentially methylated region (DMR) that encompasses the MEG3 promoter. We exploited the normal differential methylation of the DLK1/MEG3 region to develop a rapid diagnostic PCR assay based upon an individual's epigenetic profile. We used methylation-specific multiplex PCR in a retrospective analysis to amplify divergent lengths of the methylated and unmethylated MEG3 DMR in a single reaction and accurately identified normal, maternal UPD14, and paternal UPD14 in bisulfite converted DNA samples. This approach, which is based solely on differential epigenetic profiles, may be generally applicable for rapidly and economically screening for other imprinting defects associated with uniparental disomy, determining loss of heterozygosity of imprinted tumor suppressor genes, and identifying gene-specific hypermethylation events associated with neoplastic progression.
Chromosomes, Human, Pair 14↗
Population data suggest that deletions of 1p36 are a relatively common chromosome abnormality.
Monosomy 1p36 is a relatively common chromosome deletion. Deletion of this chromosome band can be difficult to visualize using routine cytogenetic banding techniques. The use of fluorescence in situ hybridization (FISH) with telomere region-specific probes has aided in the diagnosis of patients. In this study we ascertained 62 patients with deletions of 1p36 from 61 families and collected information regarding previous chromosome analyses, mode of ascertainment, clinical indication, age at diagnosis, and parental ages. The majority of deletions occur on the maternally derived chromosome. We identified terminal deletions, interstitial deletions, derivative chromosomes, and complex rearrangements. We correlated the type of rearrangement with the parental origins. Almost 50% of the patients had at least one chromosome analysis interpreted as normal. Retrospectively, 98% of deletions could be identified by routine chromosome analysis with careful attention to chromosome 1p36. Clinical indications were variable, with developmental delay/mental retardation being the most common. Increased maternal serum alpha fetoprotein (MSAFP) was detected in four of the five prenatally diagnosed cases. Maternal age at the time of birth of the affected child was significantly lower than the general United States population mean. We suggest a multistep approach for the diagnosis and clinical evaluation in cases of monosomy 1p36.
Abnormalities, Multiple↗
Omphalocele in trisomy 3q: further delineation of phenotype.
We report a case of a patient with omphalocele, dysmorphic features, and mild developmental delay associated with a chromosomal aberration. Chromosome studies showed that the propositus carries a maternally derived unbalanced translocation der(4)t(3;4)(q27.3;q32.3), resulting in trisomy for region 3q27.3-->qter and monosomy for 4q32.3-->qter. Because the association between dup3q and omphalocele has been reported in several cases, we analyzed the data on 93 previously reported patients with partial trisomy of the long arm of chromosome 3 and compared the clinical features between the cases. The imbalance of chromosome 3 in the patient was further defined by fluorescence in situ hybridization (FISH) studies using bacterial artificial chromosome (BAC) clones. BAC clone RP11-171N2 was identified as a breakpoint-spanning clone in the patient and his mother. Based on our comparative analysis, we have delineated that the smallest region of overlap (SRO) associated with omphalocele is from BAC 171N2 to 3qter. We hypothesize that the SRO contains a gene(s) important in normal abdominal wall development and is of potential interest for further investigation.
Chromosomes, Human, Pair 3↗
Comprehensive microsatellite marker analysis contradicts previous report of segmental maternal heterodisomy of chromosome 14.
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Child↗
Survival of male patients with incontinentia pigmenti carrying a lethal mutation can be explained by somatic mosaicism or Klinefelter syndrome.
Incontinentia pigmenti (IP), or "Bloch-Sulzberger syndrome," is an X-linked dominant disorder characterized by abnormalities of skin, teeth, hair, and eyes; skewed X-inactivation; and recurrent miscarriages of male fetuses. IP results from mutations in the gene for NF-kappaB essential modulator (NEMO), with deletion of exons 4-10 of NEMO accounting for >80% of new mutations. Male fetuses inheriting this mutation and other "null" mutations of NEMO usually die in utero. Less deleterious mutations can result in survival of males subjects, but with ectodermal dysplasia and immunodeficiency. Male patients with skin, dental, and ocular abnormalities typical of those seen in female patients with IP (without immunodeficiency) are rare. We investigated four male patients with clinical hallmarks of IP. All four were found to carry the deletion normally associated with male lethality in utero. Survival in one patient is explained by a 47,XXY karyotype and skewed X inactivation. Three other patients possess a normal 46,XY karyotype. We demonstrate that these patients have both wild-type and deleted copies of the NEMO gene and are therefore mosaic for the common mutation. Therefore, the repeat-mediated rearrangement leading to the common deletion does not require meiotic division. Hypomorphic alleles, a 47,XXY karyotype, and somatic mosaicism therefore represent three mechanisms for survival of males carrying a NEMO mutation.
Alleles↗
Hereditary neuropathy with liability to pressure palsies is not a major cause of idiopathic carpal tunnel syndrome.
BACKGROUND: Carpal tunnel syndrome is a debilitating neuropathy affecting millions of individuals. Although there are published reports of familial associations of carpal tunnel syndrome, the molecular mechanisms are unknown. OBJECTIVE: To determine the prevalence and potential role of the chromosome 17 microdeletion associated with hereditary neuropathy with liability to pressure palsies in patients diagnosed as having carpal tunnel syndrome. DESIGN: Prospective study. PATIENTS AND METHODS: Since hereditary neuropathy with liability to pressure palsies may present as carpal tunnel syndrome, we evaluated 50 patients with idiopathic carpal tunnel syndrome for hereditary neuropathy with liability to pressure palsies. RESULTS: No hereditary neuropathy with liability to pressure palsies deletions were detected. CONCLUSION: Molecular genetic testing for hereditary neuropathy with liability to pressure palsies in patients with idiopathic carpal tunnel syndrome is of limited value.
Adult↗
Compensating for central nervous system dysmyelination: females with a proteolipid protein gene duplication and sustained clinical improvement.
A submicroscopic duplication that contains the entire proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease, an X-linked central nervous system dysmyelinating disorder. Previous studies have demonstrated that carrier females for the duplication are usually asymptomatic. We describe 2 unrelated female patients who present with mild Pelizaeus-Merzbacher disease or spastic paraplegia. In 1 patient, clinical features as well as cranial magnetic resonance imaging and brainstem auditory evoked potential results have improved dramatically over a 10-year period. The other patient, who presented with spastic diplegia and was initially diagnosed with cerebral palsy, has also shown clinical improvement. Interphase fluorescent in situ hybridization identified a proteolipid protein gene duplication in both patients. Interphase fluorescent in situ hybridization analyses of the family members indicated that the duplication in both patients occurred as de novo events. Neither skewing of X inactivation in the peripheral lymphocytes nor proteolipid protein gene coding alterations were identified in either patient. These findings indicate that, occasionally, females with a proteolipid protein gene duplication can manifest an early-onset neurological phenotype. We hypothesize that the remarkable clinical improvement is a result of myelin compensation by oligodendrocytes expressing one copy of proteolipid protein gene secondary to selection for a favorable X inactivation pattern. These findings indicate plasticity of oligodendrocytes in the formation of central nervous system myelin and suggest a potential role for stem cell transplantation therapies.
Brain↗
Prenatal diagnosis of a homologous Robertsonian translocation involving chromosome 15.
We report the prenatal diagnosis of a fetus with a de novo Robertsonian translocation: 45,XY,der(15;15)(q10;q10). Although Robertsonian translocations are common chromosomal rearrangements, those involving homologous chromosomes are infrequent. Since chromosome 15 is imprinted, uniparental disomy (UPD) is a concern when chromosomal rearrangements involving chromosome 15 are identified. In the present case, UPD studies showed normal biparental inheritance. In contrast to the fact that most homologous acrocentric rearrangements are isochromosomes, these results indicate postzygotic formation of a Robertsonian translocation between biparentally inherited chromosomes 15.
Adult↗
Prenatal interphase FISH diagnosis of PLP1 duplication associated with Pelizaeus-Merzbacher disease.
A submicroscopic genomic duplication in Xq22.2 that contains the entire proteolipid protein 1 gene (PLP1) is responsible for the majority of Pelizaeus-Merzbacher disease (PMD) patients. We previously developed an interphase FISH assay to screen for PLP1 duplications in PMD patients using peripheral blood and lymphoblastoid cell lines. This assay has been utilized as a clinical diagnostic test in our cytogenetics laboratory. To expand usage of the interphase FISH assay to prenatal diagnosis of PLP1 duplications, we examined three PMD families with PLP1 duplications utilizing aminiotic fluid samples. In two families the FISH assay revealed fetuses with PLP1 duplications, whereas the other fetus showed a normal copy number of PLP1. Haplotype analyses, as well as an additional FISH analysis using postnatal blood samples, confirmed the results of the prenatal analyses. Our study demonstrates utility of the interphase FISH assay in the prenatal diagnosis of PLP1 duplications in PMD.
Amniotic Fluid↗
Confined placental mosaicism for trisomy 14 and maternal uniparental disomy in association with elevated second trimester maternal serum human chorionic gonadotrophin and third trimester fetal growth restriction.
A case of confined placental mosaicism (CPM) and maternal uniparental isodisomy 14 identified after placental karyotype revealed trisomy 14 in a newborn with intrauterine growth restriction (IUGR) and minor dysmorphic features is reported. During the second trimester of the pregnancy, multiple marker screening revealed an increased risk for Down syndrome of > 1 in 10. The maternal serum human chorionic gonadotrophin (MShCG) was markedly elevated at 4.19 MoM. Amniocentesis revealed a normal 46,XX karyotype. Fetal growth restriction has been associated with elevated MShCG and placental aneuploidy with CPM for chromosomes 2, 7, 9 and 16. The present case of CPM for chromosome 14 was also associated with fetal growth restriction and elevated second trimester MShCG, suggesting a common link. Further studies need to be done to determine if indeed elevation of second trimester MShCG is associated with increased risk of CPM. The present case again demonstrates the need to perform placental karyotype in unexplained fetal growth restriction.
Adult↗
Identification of a human brain-specific gene, calneuron 1, a new member of the calmodulin superfamily.
The calmodulin superfamily includes the calmodulins, calcium-binding proteins, and related genes. Herein, we describe the cloning and characterization of human calneuron 1 (CALN1). CALN1 encodes a novel neuron-specific protein that maps to chromosome 7q11. CALN1 spans a large genomic region (>360 kb). Sequence comparison shows significant similarity with the calmodulin superfamily of genes, especially in the two conserved EF-hand motifs. The mouse orthologous gene (Caln1) shows little prenatal expression, with highest expression at Postnatal Day 21. In situ hybridization to adult mouse brain shows high expression in the cerebellum, hippocampus, and cortex. The high expression of this gene exclusively in brain, the developmental changes in expression levels, the high homology with calmodulin which indicates a potential role in signal transduction, and the cellular localization of the mRNA suggest that CALN1 has a significant role in the physiology of neurons and is potentially important in memory and learning.
Amino Acid Sequence↗
Terminal deletion of 1p36.
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Abnormalities, Multiple↗
Identification and characterization of satellite III subfamilies to the acrocentric chromosomes.
The centromeres and the short arms of the five pairs of acrocentric chromosomes in humans are composed of tandemly ordered repetitive DNA. Previous studies have suggested that the exchanges between acrocentric chromosomes have resulted in concerted evolution of different DNA sequences in their short arms. The acrocentric chromosomes are clinically relevant since they are involved in Robertsonian translocation formation and non-disjunction resulting in aneuploidy. Here we have identified seven new satellite III repetitive DNA subfamilies, determined their nucleotide sequences and established their chromosomal distributions on the short arms of the acrocentric chromosomes. Knowledge of these related sequences may help to elucidate the molecular basis of Robertsonian translocation formation.
Base Sequence↗
Satellite III sequences on 14p and their relevance to Robertsonian translocation formation.
Robertsonian translocations (ROBs) are the most common rearrangements in humans, contributing significantly to genetic imbalance, fetal wastage, mental retardation and birth defects. Rob(14q21q) and rob(13q14q), which are formed predominantly during female meiosis, comprise the majority (approximately 85%) of all ROBs. Previous studies have shown that the breakpoints are consistently located within specific regions of the proximal short arms of chromosomes 13, 14, and 21. The high prevalence of these translocations, the consistent breakpoints found, and the fact that roughly 50% of cases occur sporadically suggest that the sequences at or near the breakpoints confer susceptibility to chromosome rearrangement and that the rearrangements occur through a specific mechanism. To investigate this hypothesis, we developed hamster-human somatic cell hybrids derived from de novo rob(14q21q) patients that contained the translocated chromosome segregated from the other acrocentric chromosomes. We determined the physical order of five satellite III subfamilies on 14p, and investigated their involvement in formation of these de novo translocations.
Abnormalities, Multiple↗