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PubMed1990

Derivation of clones from the choroideremia locus by preparative field inversion gel electrophoresis.

By making use of preparative field inversion gel electrophoresis, we have constructed a lambda ZAP library that is highly enriched for sequences from the choroideremia locus. In vivo excision of pBluescript SK(-) constructs from lambda ZAP obviates the subcloning of DNA inserts and allows for rapid processing of several hundred recombinants. From a 625 kb Sfil fragment we isolated 7 clones that were physically mapped using microdeletions associated with the disease. One of these clones is located within, or just telomeric to, the choroideremia gene and detects two restriction fragment length polymorphisms (RFLPs). Another clone detects a RFLP which maps centromeric to the disease locus. Together these probes should improve the reliability of linkage analysis in choroideremia families and should pave the way for the isolation of the choroideremia gene.

Animals↗
PubMed1994

Familial blepharophimosis with ovarian dysfunction.

Three cases including two sisters and one brother with blepharophimosis are described. Their father also had blepharophimosis. Moreover, the elder sister initially presented with resistant ovary syndrome and thereafter true premature menopause, while the younger one presented with resistant ovary syndrome. The explanation for the association of blepharophimosis with primary ovarian dysfunction is unknown, but the possibility of a microdeletion of genetic material containing two geographically associated, but independent genes could not be confirmed or excluded. All families affected by blepharophimosis should be counselled about the high incidence of ovarian dysfunction and female infertility, at least in one form of the syndrome.

Adult↗
PubMed2001

Positive and negative selection in the DAZ gene family.

Because a microdeletion containing the DAZ gene is the most frequently observed deletion in infertile men, the DAZ gene was considered a strong candidate for the azoospermia factor. A recent evolutionary analysis, however, suggested that DAZ was free from functional constraints and consequently played little or no role in human spermatogenesis. The major evidence for this surprising conclusion is that the nonsynonymous substitution rate is similar to the synonymous rate and to the rate in introns. In this study, we reexamined the evolution of the DAZ gene family by using maximum-likelihood methods, which accommodate variable selective pressures among sites or among branches. The results suggest that DAZ is not free from functional constraints. Most amino acids in DAZ are under strong selective constraint, while a few sites are under diversifying selection with nonsynonymous/ synonymous rate ratios (d(N)/d(S)) well above 1. As a result, the average d(N)/d(S) ratio over sites is not a sensible measure of selective pressure on the protein. Lineage-specific analysis indicated that human members of this gene family were evolving by positive Darwinian selection, although the evidence was not strong.

Amino Acid Substitution↗
PubMed1994

Cardiovascular molecular genetics.

This monograph reviews advances in understanding the genetic basis of heritable disorders of the heart and vasculature, including hypertrophic cardiomyopathy, Marfan syndrome, conotruncal malformations, atrioventricular septal defects, supravalvular aortic stenosis, and the field defects associated with DiGeorge and velocardiofacial syndromes. The prognostic value and the functional effects of beta myosin heavy chain gene mutations in familial hypertrophic cardiomyopathy are discussed. The relation between Marfan syndrome and fibrillin mutations and that between supravalvular aortic stenosis and William syndromes and elastin mutations are reviewed, as is the presence of microdeletions in 22q11 in DiGeorge syndrome, velocardiofacial syndrome, and nonsyndromic patients with conotruncal malformations. The relation between neural crest cells and field defects are considered in the context of the genetic basis of Patch, a mutation that results in abnormal neural crest cell migration and conotruncal malformations. The role of transforming growth factor beta isoforms in cardiac morphogenesis is considered in the light of apparently normal morphogenesis in transforming growth factor beta 1 null mice.

Animals↗
PubMed1995

The molecular genetics of cardiovascular disease.

The following consideration of this past year's published studies uses the cited reports as important examples of the ongoing characterization of the molecular basis of cardiac disease and the process of cardiac development. Mutations in cardiac troponin T and alpha-tropomyosin have been identified in familial hypertrophic cardiomyopathy, as have new beta-myosin heavy chain gene mutations. The general relation between beta-myosin heavy chain gene mutations that produce a charge change versus conservative amino acid replacements and sudden death remains unresolved. New fibrillin 1 gene mutations have been identified in patients with Marfan syndrome, the neonatal form of Marfan syndrome, and ectopia lentis. The same mutation is rarely found in more than one family. The association of supravalvar aortic stenosis and elastin gene mutations was further strengthened. The complexity of the relation between dystrophin mutations and the cell-specific loss of dystrophin expression can result in patients having cardiomyopathy and no myopathy. X-chromosome inactivation was shown to be the basis of cardiomyopathy in women with a single mutated dystrophin allele. New candidate genes that control cardiac morphogenesis and myocyte differentiation were proposed. New evidence to support 22q11 microdeletions as a common basis of nonsyndromic conotruncal malformations was published. These studies represent an important beginning. Although mutant genes have been recognized in affected individuals with various syndromes and congenital cardiac abnormalities, our understanding of how a genotype yields a given phenotype remains to be established.

Adult↗
PubMed2000

Genetics and male infertility.

This article reviews chromosomal and genetic disorders in the context of male fertility. Particular emphasis is on those disorders, which are encountered, in clinical practice including Klinefelter's syndrome, Kallman's syndrome, Androgen insensitivity, Y microdeletions, Y fertility gene deletions, and cystic fibrosis gene mutations. These disorders are discussed in relation to the aetiology of male fertility and also risks to children who are born of fathers with these disorders. A list of fathers' categories is proposed for outcome studies for children born after IVF-ICSI. Finally a question is proposed to catalyse debate about germ line therapy.

Chromosome Aberrations↗
PubMed1998

A new mutation in the POU3F4 gene in a Japanese family with X-linked mixed deafness (DFN3).

OBJECTIVE: The molecular defect in patients with X-linked mixed deafness showing a perilymphatic gusher at stapedectomy (DFN3) has been attributed to mutations in the POU3F4 gene. This study aimed to clarify an allelic variant of this gene. STUDY DESIGN: This was a genetic study of a single Japanese family with DFN3. METHODS: Products of a polymerase chain reaction (PCR) were subjected to single-strand conformation polymorphism (SSCP) analysis. Direct sequencing of PCR products from patients and carriers showing SSCP variants was performed using the fluorescent dideoxy termination method and a sequencer. RESULTS: Sequencing of the PCR product revealed a 6-base deletion (TTCAAA) at nucleotides 601 to 606, resulting in a two-amino-acid deletion in the POU3F4 protein, (phenylalanine and lysine at amino acid residues 201 and 202). The deletion was adjacent to the site of a nonsense mutation previously described. CONCLUSION: Microdeletions at a previously undescribed location account for some clinically important POU3F4 mutations.

Asian People↗
PubMed1983

Isolation of DNA fragments from chromosome 13.

A number of patients with retinoblastoma have a deletion of chromosome 13. Comparison of the deleted segments from different individuals reveals that all deletions involve chromosome band 13q14. This observation has lead to the hypothesis that in this region is a gene of genes important in the etiology of retinoblastoma. As a first step toward understanding those genes, the authors successfully isolated five DNA fragments from chromosome 13 using recombinant DNA techniques. The DNA fragments from chromosome 13 will be useful in identifying DNA polymorphic sites that are linked to the retinoblastoma locus tentatively assigned to 13q14. Such DNA polymorphisms will be important in the genetic counselling of families with retinoblastoma. These chromosome 13q14 fragments also may be useful in searching for microdeletions of 13q14.

Animals↗
PubMed1994

Genetic basis of DiGeorge and velocardiofacial syndromes.

DiGeorge syndrome and velocardiofacial syndrome have been shown to be associated with microdeletions of chromosome 22q11. More recently, 22q11 deletions have also been detected in individuals with some types of conotruncal cardiac defects as well as conotruncal anomaly face syndrome. Fluorescence in situ hybridization of metaphase chromosomes using cosmid probes from the DiGeorge chromosomal region has been shown to be an efficient method for the detection of 22q11 deletions in at-risk patients, families, and pregnancies. This review summarizes recent cytogenetic, molecular, and phenotypic studies of patients with DiGeorge syndrome and velocardiofacial syndrome as well as recent efforts to identify genes within 22q11 that may play a role in the development of the phenotypic features observed in these disorders.

Abnormalities, Multiple↗
PubMed2001

22q11.2 deletion syndrome: DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes.

A microdeletion of chromosome 22q11.2 is found in most patients with velocardiofacial syndrome, DiGeorge syndrome, and conotruncal anomaly face syndrome, and in some patients with Cayler cardiofacial and autosomal dominant Opitz-G/BBB syndromes. A wide spectrum of clinical findings accompanies the 22q11.2 deletion, without genotype or phenotype correlation even among affected family members. Classic features are dysmorphic facies, conotruncal cardiac defects, hypocalcemic hypoparathyroidism, T-cell mediated immune deficiency, and palate abnormalities. Less well recognized are learning, speech, feeding, and psychiatric disorders, and renal and musculoskeletal defects. Parathyroid and immune deficiencies in the same individual can progress or resolve with time. The 22q11.2 deletion can be inherited as an autosomal dominant or arise as a de novo deletion or translocation. Fluorescent in situ hybridization using cosmid probes mapping to the DiGeorge chromosomal region is a widely available method to detect the 22q11.2 deletion in metaphase chromosomes from cultured lymphocytes, amniocytes, or chorionic villi. The ubiquitin-fusion-degradation-1-like gene, expressed in embryonic branchial arches and in the conotruncus, appears to play a prominent role in the pathogenesis of the 22q11.2 deletion syndrome.

Child↗
PubMed2002

Monosomy 1p36--a recently delineated, clinically recognizable syndrome.

Monosomy 1p36 is a recently delineated contiguous gene syndrome, which is now considered to be one of the most common subtelomeric microdeletion syndromes. We report four unrelated patients with subtle deletions within 1p36 confirmed by high resolution karyotyping and FISH. All exhibited severe psychomotor retardation. Microcephaly, seizures, and visual impairment occurred in three subjects. Results of a first routine karyotyping were unrevealing in three probands. The diagnosis was primarily suggested on the basis of a distinct pattern of facial anomalies in all except the first case. This report illustrates that monosomy 1p36 may be recognized clinically, at least in some patients, whereas the diagnosis is easily missed on routine karyotype.

Child↗
PubMedDate not supplied

Heterotaxy: associated conditions and hospital-based prevalence in newborns.

PURPOSE: To provide insight into the possible etiology and prevalence of heterotaxy, we studied conditions associated with heterotaxy in a consecutive hospital population of newborns. METHODS: From 1972 to March, 1999 (except February 16, 1972 to December 31, 1978), 58 cases of heterotaxy were ascertained from a cohort of 201,084 births in the ongoing Active Malformation Surveillance Program at the Brigham and Women's Hospital. This registry includes livebirths, stillbirths, and elective abortions. Prevalence among nontransfers (i.e., patients whose mothers had planned delivery at this hospital) was calculated as approximately 1 per 10,000 total births (20 of 201,084). RESULTS: We analyzed a total of 58 patients consisting of 20 (34%) nontransfers and 38 (66%) transfers. Patients were categorized by spleen status as having asplenia (7 nontransfers, 25 total), polysplenia (8, 20), right spleen (4, 11), normal left (0, 1), and unknown (1, 0). Among the 20 nontransfer and 59 total heterotaxy patients, the following associated medical conditions were present: chromosome abnormality (1 nontransfer, 2 total), suspected Mendelian or chromosome microdeletion disorder (1 nontransfer, 6 total), and maternal insulin-dependent diabetes mellitus (1 nontransfer, 2 total). There were 6 twins (1 member each from 6 twin pairs including 1 dizygous, 4 monozygous, 1 conjoined; 2 were nontransfers). An associated condition occurred in 5 (25%) nontransfer and 16 (28%) total patients, or among 10 of 53 singleton births (19%). CONCLUSIONS: Although most cases of heterotaxy in this series were sporadic events, an associated condition was present in about one-fourth of the cases. Not all of these conditions would be considered causative etiologies. Based on this small series alone, maternal insulin-dependent diabetes cannot be viewed as a risk factor for heterotaxy. However, the specific association of diabetes with polysplenia with/without left atrial isomerism is noteworthy, and adds weight to animal and epidemiologic case-control data.

Abnormalities, Multiple↗
PubMedDate not supplied

Auxological evaluation in patients with DiGeorge/velocardiofacial syndrome (deletion 22q11.2 syndrome).

PURPOSE: Patients with microdeletion of chromosome 22q11.2 (del22q11) were studied, in order to evaluate auxological parameters and to correlate growth patterns with the presence of main clinical characteristics of the syndrome. METHODS: Between January 1995 and March 2000, auxological parameters (weight, height, head circumference, and bone age) of 73 patients with del22q11 were collected. Five subgroups of patients were distinguished: Group I (37 patients) included patients aged between 0.3 and 4 years, Group II (20 patients) included patients aged between 5 and 10 years, Group III (16 patients) included patients aged between 11 and 16.3 years. The presence or absence of some clinical features was correlated to growth patterns. RESULTS: Weight: in Group I, 5 of 37 (13.5%) patients were below the 3rd percentile, 29 of 37 (78.3%) were below the mean percentile, none was overweight; in Group II, 13 of 20 (65%) patients were between the 10th and the 50th percentiles; in Group III, weight corresponded to the 97th percentile in 5 of 16 (31.2%) patients, and in 2/16 (12.5%) adolescents, the weight measurements were even above the 97th percentile. Height: short stature was detected in 7 of 73 (9.6%) of the total patients; the patients with short stature were all < 10 years old; the height was within the normal age in all adolescent patients. Head circumference: it was below the 3rd percentile in 7 of 73 (9.6%), between the 3rd and the 25th percentiles in 36 of 73 (49.3%) patients, between the 25th and the 75th percentiles in 20 of 73 (27.3%) patients, and between the 75th and the 97th percentiles in 10 of 73 (13.7%) patients. Bone age: mean +/- SD bone age was -0.25 +/- 0.78 years. Comparisons: the only statistically significant correlation was that between the presence of feeding difficulties and underweight. CONCLUSION: Auxological parameters of children with del22q11 are characterized by: (1) weight deficiency in the first years of age, (2) weight normalization in the following years, (3) development of obesity in adolescence, (4) short stature in 10% of the patients, (5) normal height in adolescents, (6) slight delay in bone age in infancy, (7) microcephaly in 10% of the patients.

Adolescent↗
PubMedDate not supplied

Taking advantage of early diagnosis: preschool children with the 22q11.2 deletion.

PURPOSE: The purpose of this study is to review the neurodevelopmental outcome of infants and preschoolers with a 22q11.2 microdeletion and to discuss the our clinical observations of clinical implications for educational and therapeutic interventions. METHODS: One hundred twelve children (4 to 70 mos) with the 22q11.2 deletion were assessed using standardized tests (Bayley Scales of Infant Development-II, Preschool Language Scales, Wechsler Preschool and Primary Scales of Intelligence-Revised). RESULTS: Fifty-four percent of the children were significantly delayed, 24% had mild delay, 22% had average cognitive development, and 80% were below average in language development. Delays are not explained by cardiac defects or palatal defects. CONCLUSION: Developmental delays, mild hypotonia, language and speech delays, and feeding disorders are common, and this finding indicates the need for early intervention services beginning in infancy for children with the 22q11.2 deletion.

Abnormalities, Multiple↗
PubMedDate not supplied

Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis syndrome [del(17)(p11.2p11.2)].

PURPOSE: This report delineates the phenotypic features in a cohort of 58 individuals with Smith-Magenis syndrome (SMS) and compares features of patients with the common microdeletion to those of patients with variable sized deletions, and the three previously reported patients who harbor a mutation in RAI1 (retinoic acid induced 1). METHODS: From December 1990 thru September 1999, 58 persons with SMS were enrolled in a 5-day multidisciplinary clinical protocol at the General Clinical Research Center (GCRC), Texas Children's Hospital. Each patient had a cytogenetically evident deletion in 17p11.2. RESULTS: Of the 51 patients in whom the molecular extent of the chromosomal deletion could be delineated by pulsed-field gel electrophoresis (PFGE) and/or fluorescent in situ hybridization (FISH), 39 (approximately 76%) had the common SMS deletion. Smaller or larger deletions were seen in approximately 12% and approximately 10% of patients, respectively, and 1 patient had a complex chromosomal rearrangement including a deletion in 17p11.2. Parent of origin was determined by polymorphic marker analysis in a subset of patients: maternal approximately 43%, paternal approximately 57%. All patients had impaired cognitive and adaptive functioning and had at least one objective measure of sleep disturbance. Other common features (seen in >50% of patients) include short stature, ophthalmological, and otolaryngological anomalies, hearing impairment, abnormal EEG, and scoliosis. Cardiac and renal anomalies were seen in approximately 45% and approximately 19% of patients, respectively. There are no statistically significant differences in the incidence of these abnormalities in patients with the common deletion compared to those patients with smaller or larger sized deletions. CONCLUSIONS: Despite a common deletion size in 76% of patients with SMS, the only constant objectively defined features among these patients are sleep disturbances, low adaptive functioning, and mental retardation. There is no pathognomonic clinical feature, no characteristic cardiovascular defect, renal anomaly, otolaryngological or ophthalmic abnormality in SMS.

Adolescent↗
PubMedDate not supplied

Familial 22q11.2 deletions in DiGeorge/velocardiofacial syndrome are predominantly smaller than the commonly observed 3Mb.

PURPOSE: DiGeorge/velocardiofacial syndrome (DG/VCFS) is the most common cytogenetically characterized microdeletion of 22q11.2 region. In approximately 90% of patients, the deletion size is 3 Mb, whereas the remaining range from 1.5 to 2.5 Mb. The purpose of this study was to test the hypothesis that small deletions may be more easily tolerated in a familial fashion than larger deletions, especially for this syndrome. METHOD: Sixteen FISH probes designed from bacterial artificial chromosomes (BACs) and P1 artificial chromosomes (PACs) mapped to 22q11.2 were used to determine the deletion sizes in 22 individuals from ten families with familial 22q11.2 deletion detected by standard FISH tests. RESULT: Seven families had deletions of < 3 Mb ( approximately 1.5 Mb) in size and 3 families had the common 3-Mb deletion. The 70% frequency of smaller sized deletions among this group of patients with familial del(22)(q11.2) is significantly higher than that reported among unselected group of patients with del(22)(q11.2) (P < 0.0001, Fisher exact test). CONCLUSION: Familial del(22)(q11.2) are predominantly smaller than the common deletion size of 3 Mb, indicating that there may be some underlying mechanisms that favor parent-to-child transmission of smaller deletions in individuals with del(22)(q11.2), therefore, underscoring the need to exclude a familial basis in cases of del(22)(q11.2) smaller than 3 Mb.

Chromosome Deletion↗
PubMed2006

Acute health events in adult patients with genetic disorders: the Marshfield Epidemiologic Study Area.

PURPOSE: We ascertained and reviewed acute health events occurring in 2003 among patients age 18 and greater with well-defined single gene, chromosomal, and selected multifactorial conditions within the Marshfield Epidemiologic Study Area. METHODS: Of 47,077 adult Marshfield Epidemiologic Study Area Central cohort members, 1,831 (3.9%) had been given at least one of 71 ICD-9 codes appropriate for genetic diagnoses of interest. Physician review narrowed this to 591 (1.3%) validated patients for the study. Of the 591, 527 (89.2%) patients registered 6,849 visits, which were manually reviewed to delineate acute, relevant health events in the urgent care and primary care provider setting. RESULTS: A total of 244 acute relevant health events among 126 patients corresponding to 58 different genetic conditions were observed. Acute relevant health events corresponded to 3.4% of the total health events in patients identified with genetic problems. Categories of genetic conditions with the highest frequencies of acute relevant health events included chromosomal and microdeletion syndromes (21.3%), hematologic disorders (11.5%), muscular dystrophies (8.6%), and connective tissue disorders (10.2%). CONCLUSIONS: These data have multiple applications and implications in addressing the natural history, long-term medical needs and financial impact of adult patients with genetic conditions.

Acute Disease↗