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PubMed1986

Lethal multiple pterygium syndrome: report of a new case with hydranencephaly.

A 28-week male fetus with the cardinal signs of the lethal multiple pterygium syndrome (multiple pterygia, congenital joint contractures, lung hypoplasia, facial abnormalities, and hydrops) is reported here. In addition, he had hydranencephaly, an anomaly not yet reported in this group of conditions. This potentially new form of the lethal multiple pterygium was detected prenatally by ultrasound examination. In discussing the case, we consider the probable autosomal recessive inheritance pattern and raise questions about the etiology and heterogeneity of this syndrome.

Anencephaly↗

PubMed1990

A de novo X;3 translocation in Rett syndrome.

Rett syndrome is a neurodegenerative disorder that occurs exclusively in females. The syndrome is sporadic in most cases with the exception of a few familial cases with an inheritance pattern through maternal lines. These observations raised the possibility that Rett syndrome may be due to an X-linked dominant mutation which is lethal in the male. To evaluate this hypothesis, we have systematically performed high-resolution chromosome analysis on 28 patients with Rett syndrome searching for deletions and/or translocations. In one patient, a de novo balanced translocation was observed with the chromosome constitution of 46,X,t(X;3) (p22.11;q13.31). This finding supports the hypothesis of an X-linked dominant mutation and suggests that the Rett gene might map to distal Xp21 or proximal Xp22.

Child, Preschool↗

PubMed1991

Biochemical and clinical characterization of prealbuminCHICAGO: an apparently benign variant of serum prealbumin (transthyretin) discovered with high-resolution two-dimensional electrophoresis.

We report identification, biochemical, clinical, and genetic studies of an apparently benign, electrophoretic variant of serum prealbumin (PALB, transthyretin, TTR) in a North American kindred of Swedish ancestry. The variant polypeptide stems from a C to T point mutation in exon 4 which results in methionine instead of threonine at position 119 of the mature molecule. It was discovered incidentally in a girl with classic alpha-1-anti-trypsin (A1AT) deficiency and her father during diagnostic A1AT phenotyping by ISO-DALT high-resolution two-dimensional electrophoresis (2DE). Twelve relatives in the four-generation paternal kindred, including five individuals who were heterozygous for the variant prealbumin, were studied. In each of these five heterozygotes, the variant allele product was equimolar and isoelectric with the normal protein, yet migrated with an apparently lower mass in the SDS-PAGE dimension. The inheritance pattern was consistent with autosomal dominant transmission. Histories and physical examinations showed no evidence of amyloidosis, as has been observed with other variants of prealbumin. Mean values of serum prealbumin and retinol binding protein levels were higher in the carriers as compared to the normal relatives in the family, but the difference was not statistically significant. Thyroid hormone levels and distribution of thyroxine and triiodothyronine among binding proteins in serum were within reference limits. Four members of the lineage had dominant, scalp-restricted keratinaceous cysts, yet only three of these four individuals had the variant. We counseled the family that this is likely a benign variant with regard to amyloidosis-related morbidity or shortened life span, although senile effects cannot be entirely ruled out. The provisional designation assigned to this allele is PALBCHICAGO. The substitution of methionine at position 119, as predicted by the DNA sequence, was confirmed by amino acid sequencing of CNBr and tryptic peptides. This substitution occurs at a CpG dinucleotide that may be a point mutational "hot spot," as has been postulated for the methionine-30 and isoleucine-122 PALB variants. The apparently lower mass of the variant probably results from a more compact conformation in SDS. With the exception of histidine-58, a charge substitution, all other amyloidosis-related prealbumin variant polypeptides had normal mobility in the ISO-DALT 2DE system.

Adult↗

PubMed1993

Sagittal craniosynostosis, Dandy-Walker malformation, and hydrocephalus: a unique multiple malformation syndrome.

The Dandy-Walker malformation and craniosynostosis have each been described as isolated occurrences and as components of multiple malformation syndromes. The purpose of this report is to delineate the characteristics of a multiple malformation syndrome of Dandy-Walker malformation and sagittal craniosynostosis. The inheritance pattern appears to be autosomal dominant.

Abnormalities, Multiple↗

PubMed1994

Genetic epidemiologic study of hearing loss in an adult population.

Previous population studies of hearing loss have been limited to children with moderate to profound impairment, and have reported that heritability accounts for at least 50% of congenital or early-onset cases. The present study was designed to assess genetic factors associated with late-onset hearing impairment in an adult population. A brief family history and audiologic questionnaire was sent to approximately 11,200 members of the consumer organization, Self Help for the Hard of Hearing, Inc., and 4,039 questionnaires were returned. All respondents reported having at least one previous audiologic exam. Reported data were verified against audiograms when available. Regardless of the reported causes, 49% of early-onset cases (< or = 20 years of age) had one or two parent(s) with some form of hearing loss compared with 62% in later-onset cases. As expected, mean age at onset was substantially younger for cases with positive family histories than cases with negative family histories. Results from nuclear segregation analysis showed that fully recessive and dominant models failed to explain the early- or late-onset hearing loss data. In this nationwide survey, the large proportion of cases with positive family histories clearly indicates the importance of genetic factors in adult-onset forms of hearing loss. Comparison with younger-onset cases will permit further delineation of differences in inheritance patterns. This study should identify more homogeneous groups of adult-onset families for further genetic study, and provide empiric information for use in genetic counselling.

Adult↗

PubMed1995

Duplication and loss of chromosome 21 in two children with Down syndrome and acute leukemia.

Acute leukemia in Down syndrome (DS) is often associated with additional changes in the number or structure of chromosome 21. We present two DS patients whose leukemic karyotypes were associated with changes in chromosome 21 ploidy. Patient 1 developed acute lymphocytic leukemia (type L1); disomy for chromosome 21 was evident in all blast cells examined. Loss of the paternal chromosome in the leukemic clone produced maternal uniparental disomy with isodisomy over a 25-cM interval. The second patient had acute monoblastic leukemia (type M5) with tetrasomy 21 in all leukemic cells. DNA polymorphism analysis showed duplicate paternal chromosomes in the constitutional genotype. The maternal chromosome was subsequently duplicated in the leukemic clone. The distinct inheritance patterns of chromosome 21 in the blast cells of these patients would appear to indicate that leukemogenesis occurred by different genetic mechanisms in each individual.

Child, Preschool↗

PubMed1995

Familial microtia with meatal atresia and conductive deafness in five generations.

We describe a large family with congenital microtia, auditory meatal atresia and conductive deafness. The pedigree suggests autosomal dominant inheritance with variable expression and low penetrance. The literature is also reviewed to describe the inheritance pattern and clinical spectrum noted in this rare syndrome so far. The family is unique because the set of otologic anomalies in five generations was associated with renal cysts in one of the affected members, suggesting that this oto-renal (OR) syndrome may represent a variable expression of the branchio-oto-renal (BOR) syndrome. However, the probability is that this dominant malformation syndrome is a distinct entity.

Child↗

PubMed1995

Confirmation of locus heterogeneity in the pure form of familial spastic paraplegia.

Familial spastic paraplegia (FSP), characterized by progressive spasticity of the lower extremities, is in its "pure" form generally of autosomal dominant inheritance pattern. Hazan et al. [Nat Genet 5:163-167, 1993] reported tight linkage of a large FSP family to the highly polymorphic microsatellite marker D14S269 with z (theta) = 8.49 at theta = 0.00 They further demonstrated evidence for locus heterogeneity when they showed that 2 FSP families were unlinked to this region. We have subsequently studied 4 FSP families (3 American, one British) and excluded the disease locus in these families for approximately 30 cM on either side of D14S269, thereby confirming evidence for locus heterogeneity within the spastic paraplegia diagnostic classification.

Chromosomes, Human, Pair 14↗

PubMed2001

Diseases caused by nuclear genes affecting mtDNA stability.

Diseases caused by nuclear genes that affect mitochondrial DNA (mtDNA) stability are an interesting group of mitochondrial disorders, involving both cellular genomes. In these disorders, a primary nuclear gene defect causes secondary mtDNA loss or deletion formation, which leads to tissue dysfunction. Therefore, the diseases clinically resemble those caused by mtDNA mutations, but follow a Mendelian inheritance pattern. Several clinical entities associated with multiple mtDNA deletions have been characterized, the most frequently described being autosomal dominant progressive external ophthalmoplegia (adPEO). MtDNA depletion syndrome (MDS) is a severe disease of childhood, in which tissue-specific loss of mtDNA is seen. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) patients may have multiple mtDNA deletions and/or mtDNA depletion. Recent reports of thymidine phosphorylase mutations in MNGIE and adenine nucleotide translocator mutations in adPEO have given new insights into the mechanisms of mtDNA maintenance in mammals. The common mechanism underlying both of these gene defects could be disturbed mitochondrial nucleoside pools, the building blocks of mtDNA. Future studies on MNGIE and adPEO pathogenesis, and identification of additional gene defects in adPEO and MDS will provide further understanding about the mammalian mtDNA maintenance and the crosstalk between the nuclear and mitochondrial genomes.

Blotting, Southern↗

PubMed1991

Mitochondrial DNA sequence analysis in congenital myotonic dystrophy.

Mitochondrial genetic modifying factors have been suspected in several autosomally inherited diseases. The congenital variant of myotonic dystrophy, in which there is striking maternal inheritance pattern, is a likely candidate disease. To investigate this possibility, we sequenced completely the mitochondrial genome in 2 patients with congenital myotonic dystrophy. Comparison of the two sequences with control data failed to reveal a specific nucleotide variant or length variant in this disease. We conclude that a mitochondrial genetic modifying factor is not present in congenital myotonic dystrophy.

Adult↗

PubMed1996

Clinical genetic analysis of Parkinson's disease in the Contursi kindred.

We performed a clinical genetic analysis of a kindred originating in the town of Contursi in Salerno province, Italy, in which 60 individuals in 5 generations are known to have had Parkinson's disease (PD). Two previously reported autopsy cases showed typical PD with Lewy bodies. The inheritance pattern is apparently autosomally dominant with a segregation ratio of 40.1% for kindred members aged 50 years and older. The mean age at PD onset is 45.6 years (standard deviation, 13.48; range, 20-85) with a mean course to death of 9.2 years (standard deviation, 4.87; range, 2-20). Otherwise, clinical characteristics of PD in the kindred, including variance in onset age and incidence of tremor and levodopa responsiveness, are similar to those of PD in the community. The presence of tremor tended to be concordant in affected parent-child pairs, but there was no parent-child correlation for age at onset or intrasibship clustering of tremor or onset age. A suggestion of anticipation disappeared after adjustment for age-related ascertainment bias. The findings show that a presumably single mutation can produce a heterogeneous PD phenotype, even among siblings. This is consistent with the hypothesis that PD in the community may in fact be caused by such a mutation, but one producing a lower penetrance and older age at onset than those in this kindred.

Adult↗

PubMed1997

Autosomal dominant dementia with widespread neurofibrillary tangles.

Several familial dementing conditions with atypical features have been characterized, but only rarely is the neuropathology dominated solely by neurofibrillary lesions. We present a Midwestern American pedigree spanning four generations in which 15 individuals were affected by early-onset dementia with long disease duration, with an autosomal dominant inheritance pattern, and with tau-rich neurofibrillary pathology found in the brain post mortem. The average age at presentation was 55 years with gradual onset and progression of memory loss and personality change. After 30 years' disease duration, the proband's neuropathologic examination demonstrated abundant intraneuronal neurofibrillary tangles (NFTs) involving the hippocampus, pallidum, subthalamic nucleus, substantia nigra, pons, and medulla. Only sparse neocortical tangles were present and amyloid plaques were absent. The tangles were recognized by antibodies specific for phosphorylation-independent (Tau-2, T46, 133, and Alz-50) and phosphorylation-dependent epitopes (AT8, T3P, PHF-1, 12E8, AT6, AT18, AT30) in tau proteins. Electron microscopy of NFTs in the dentate gyrus and midbrain demonstrated paired helical filaments. Although the clinical phenotype resembles Alzheimer's disease, and the neuropathologic phenotype resembles progressive supranuclear palsy, an alternative consideration is that this familial disorder may be a new or distinct disease entity.

Age of Onset↗

PubMed1998

The mitochondrial DNA A8344G mutation in Leigh syndrome revealed by analysis in paraffin-embedded sections: revisiting the past.

In 1975, we presented the results of a study on a family with a constellation of features that included a chronic spinocerebellar syndrome, neuropathologically proven Leigh syndrome, and sudden death in infancy or childhood affecting several members over three generations. Inheritance was thought to be autosomal dominant. Twenty years later, we reinterpreted the inheritance pattern as maternal. Mitochondrial DNA (mtDNA) extracted from paraffin-embedded brain samples from the proband revealed the A8344G myoclonic epilepsy and ragged-red fiber (MERRF) mutation as the molecular basis for this multifaceted neurological syndrome. This re-evaluation of archival material is an instructive example of "medical archeopathology."

Adolescent↗

PubMed1995

Imprinting of IGF2, insulin-dependent diabetes, immune function, and apoptosis: a hypothesis.

Parental genomic imprinting is the phenomenon in which the behavior of a gene is modified, depending on the sex of the transmitting parent [Peterson and Sapienza (1993): Annu Rev Genet 27:7-31]. Recent observations have revealed that the inheritance patterns, age-of-onset, severity, and etiology of certain human diseases can be explained by aberrations in the establishment or the maintenance of the imprint. Examples include the Prader-Willi, Angelman, and Beckwith-Wiedemann syndromes [Nicholls (1994): Am J Hum Genet 54:733-740], malignancy [Sapienza (1990): Biochim Biophys Acta 1072:51-61; Feinberg (1993): Nat Genet 4:110-113], and insulin-dependent diabetes mellitus (IDDM) [Julier et al. (1994) Nature 354:155-159; Bennett et al. (1995) Nat Genet 9:284-292]. We review the evidence that implicates an imprinted gene in the INS-IGF2 region of chromosome 11p15 in the etiology of IDDM (referred to as the IDDM2 locus) and show that in human fetal pancreas, INS is not imprinted, thus providing an argument against INS as the candidate gene. We also examine imprinting effects on the expression of IGF2 in components of the human immune system believed to be important in IDDM and show imprinted expression in fetal thymus as early as 15 weeks gestation. We demonstrate further that in the circulating mononuclear cells of two individuals, lectin-stimulated IGF2 transcription was biallelic, indicating relaxation of imprinting, whereas in one individual, transcription was monoallelic. Finally, we review the current available data supporting a role for insulin-like growth factor-II (IGF-II) in the immune system and, more specifically, discuss the evidence supporting a role for the IGFs in the prevention of apoptosis. These data have led us to formulate a novel hypothesis that could mechanistically explain the involvement of the IDDM2 locus in the pathogenesis of IDDM.

Apoptosis↗

PubMed1991

Preferrential rearrangement in normal rabbits of the 3' VHa allotype gene that is deleted in Alicia mutants; somatic hypermutation/conversion may play a major role in generating the heterogeneity of rabbit heavy chain variable region sequences.

The rabbit is unique in having well-defined allotypes in the variable region of the heavy chain. Products of the VHa locus, (with alleles a1, a2, and a3), account for the majority of the serum immunoglobulins. A small percentage of the serum immunoglobulins are a-negative. In 1986, Kelus and Weiss described a mutation that depressed the expression of the Ig VH a2 genes in an a1/a2 rabbit. From this animal the Alicia rabbit strain was developed and the mutation was termed ali. We previously showed, using Southern analysis and the transverse alternating field electrophoresis technique, that the difference between the ali rabbit and normal is a relatively small deletion including some of the most 3' VH genes. The most JH proximal 3' VH1 genes in DNA from normal rabbits of a1, a2 and a3 haplotypes encode a1, a2 and a3 molecules respectively, and it has been suggested that these genes are responsible for allelic inheritance of VHa allotypes. The present study suggests that the 3' end of the VH locus probably plays a key role in regulation of VH gene expression in rabbits because VH gene(s) in this region are the target(s) of preferential VDJ rearrangements. This raises the possibility that mechanisms such as somatic gene conversion and hypermutation are at work to generate the antibody repertoire in this species. Our data support the view that the 3' VH1 gene may be the preferred target for rearrangement in normal rabbits, and for the normal chromosome in heterozygous ali animals. However, homozygous ali rabbits with a deletion that removed the a2-encoding VH1 on both chromosomes do survive, rearrange other VH genes and produce normal levels of immunoglobulins as well as a significant percentage of B cells which bear the a2 allotype. This challenges the view that one VH gene, VH1, is solely responsible for the inheritance pattern of VHa allotypes.

Animals↗

PubMed2001

Nearly all hereditary paragangliomas in the Netherlands are caused by two founder mutations in the SDHD gene.

Hereditary paragangliomas or glomus tumors are usually benign slow-growing tumors in the head and neck region. The inheritance pattern of hereditary paraganglioma is autosomal dominant with imprinting. Recently, we have identified the SDHD gene encoding subunit D of the mitochondrial respiratory chain complex II as one of the genes involved in hereditary paragangliomas. Here, we demonstrate that two founder mutations, Asp92Tyr and Leu139Pro, are responsible for paragangliomas in 24 and 6 of the 32 independently ascertained Dutch paraganglioma families, respectively. These two mutations were also detected among 20 of 55 isolated patients. Ten of the isolated patients had multiple paragangliomas, and in eight of these SDHD germline mutations were found, indicating that multicentricity is a strong predictive factor for the hereditary nature of the disorder in isolated patients. In addition, we demonstrate that the maternally derived wild-type SDHD allele is lost in tumors from mutation-carrying patients, indicating that SDHD functions as a tumor suppressor gene.

DNA Mutational Analysis↗

PubMed1994

Allelotype of head and neck paragangliomas: allelic imbalance is confined to the long arm of chromosome 11, the site of the predisposing locus PGL.

Paragangliomas of the head and neck region are usually slow growing, benign tumors. A considerable fraction has a positive family history, and the predisposing locus, PGL, has recently been assigned to 11q22-q23. The inheritance pattern of the disease suggests that PGL undergoes maternal genomic imprinting. We have investigated 26 tumor samples from 22 patients with head and neck paragangliomas for the occurrence of loss of heterozygosity (LOH) on all non-acrocentric autosome arms. LOH was found only on chromosome 11, with a marked clustering on the distal half of the q-arm. However, in many cases the resulting allelic imbalance relative to normal DNA was weak, suggesting that only part of the tumor showed this abnormality. In all eight cases where we were able to determine the parental origin, the allele undergoing loss was maternally derived. Clonality analysis with a polymorphic marker for the X-chromosome indicated that two of three informative female cases were polyclonal, although a number of tumors carry aneuploid stemlines in DNA flow cytometry. We conclude that either tumor heterogeneity or polyclonality may explain the partial allele loss events seen in certain cases.

Alleles↗

PubMed1986

A strategy for multipoint ordering: example of the 11p markers.

The complete likelihood analysis is required to obtain the evidence for the gene order. Since the number of candidate orders increases rapidly with the number of loci and the complete analysis requires considerable computer time, a method for rapidly screening order is required. To this end, we used the program MAP83 for the initial investigation of order. This method provided a subset of orders to be further investigated by the complete likelihood method. We used PAP for these subsequent analyses. The advantage of algorithms such as MAP83 is that the basic unit of analysis is the set of pairwise LOD scores which are routinely calculated at the beginning of a linkage analysis. However, the magnitude of the log likelihood differences between orders can only be suggestive for two reasons. First, the usual assumptions for MAP83 regarding independence of the recombination fraction estimate are not met by these data and, therefore, no attempt can be made to interpret the log likelihood differences statistically. Secondly, pairwise information precludes identifying the specific inheritance pattern of each gamete, thus the information content of obligatory multiple recombinants is lost. For example, the order HBBC-ADJ-HRAS1-INS requires five double recombinants for the Utah data while the order HBBC-ADJ-INS- HRAS1 does not require any (White et al, 1985). The support for the former order over the latter is a log likelihood difference of 3.73 for the complete likelihood analysis when the HBBC locus is ignored.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromosome Mapping↗