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PubMed1999

Hypocalcemia and chromosome 22q11 microdeletion.

This review of the diagnosis, causes, prevention and treatment of hypocalcemia emphasizes the high incidence of this biological alteration in patients with 22q11 microdeletion. It also points out its large spectrum of presentation, from cases where the most prominent feature of the syndrome is hypocalcemia with hypoparathyroidism, to cases with asymptomatic, latent or late-onset hypocalcemia. Hence, the advice to perform genetic analysis of the 22q11 region in patients with late-onset or recurrent hypoparathyroidism and to systematically include serum calcium in the survey of patients with known 22q11 microdeletion, especially during infancy, adolescence and pregnancy and especially during cardiac surgery or sepsis.

Adolescent↗
PubMed2000

Genetics of male infertility: role of androgen receptor mutations and Y-microdeletions.

INTRODUCTION: Although infertility affects about 5% of the male population, its cause in most cases is uncertain. Normal spermatogenesis depends on a sequential cascade of genetic events triggered by factors encoded by the sex chromosomes. To determine the contribution of genetic aberrations to male infertility, the X-linked androgen receptor gene and the Y-chromosome were examined for mutations in a large cohort of infertile men. METHODS: Screening of the androgen receptor (AR) gene for single-stranded conformation polymorphisms, confirmation by DNA sequencing, structure-function studies with androgen-responsive reporter genes and chimeric-protein constructs were performed. Y-chromosome microdeletions screening was done with multiplex polymerase chain reaction (PCR) analyses. RESULTS: Genetic screening of over 400 patients and controls showed that defects in the androgen receptor gene lead to the production of dysfunctional receptor protein in 15% of males with abnormally low sperm production. The dozens of mutations and polymorphisms uncovered were associated with reduced intrinsic androgen receptor activity and involve principally two regions of the androgen receptor. Gene-transfer experiments implicated defective intermolecular protein-protein interactions with coactivator molecules as the cause of reduced receptor function. Submicroscopic deletions of the Y-chromosome were also been detected in about 6% of patients with severely reduced spermatogenesis. The deleted segments encoded RNA-binding proteins of unknown function and are not linked to defects in the androgen receptor. CONCLUSIONS: Mutations and polymorphisms of the AR, and Y-microdeletions cause defective sperm production and male infertility in about 20% of subfertile men. These traits can be transmitted to progeny, and counselling can be offered to affected families. Clarification of the molecular mechanisms of pathogenesis has led to rational hormonal therapy.

Animals↗
PubMed2000

[Williams syndrome (microdeletion 7q11.23), model of behavioral phenotype].

A specific behavioral phenotype is recognized in some genetic entities, particularly in microdeletion syndromes secondary to cytogenetically undetectable chromosomal deletions. Williams syndrome (WS) is a developmental disorder displaying dysmorphic signs, heart malformations and behavioral phenotype associated, in most cases, with a deletion of chromosome 7q11.23. We described physical and neuro-psychological assessment of nine cases of SW. Molecular studies were performed using Southern blot analyses or FISH, and identified a 7q11.23 deletion in all cases. Behavioral phenotype of WS is characterized by hyperactivity, engaging and jovial personality, hypersensitivity in hearing, and some elements of speech may be enhanced. Moderate mental retardation is frequently present. Previously reported studies have revealed specific cognitive deficits including deficits in language development and in long term memory, and poor visual-motor integration. Two genes, LIMK1 and STX1A, have been supposed to be implicated in determinism of WS behavioral phenotype. A specific behavioral phenotype is also demonstrated in others microdeletion syndromes, focusing attention on some chromosomal regions supposed to contain candidate genes involved in cognitive and behavioral traits.

Adult↗
PubMed2000

[Microdeletion of Y chromosome in severe olygozoospemic infertile patient].

We are reporting a 37 year old male with severe oligozoospermia and a history of infertility for thirteen years and surgery for severe unilateral varicocele. The hormonal levels for FSH, LH and T, and karyotype were within the normal range. Multiplex PCR revealed the presence of a de novo microdeletion in the azoospermia factor (AZF) c region involving the deleted in azoospermia (DAZ) and basic protein Y-2 (BPY2) genes. These results suggest that severe oligozoospermia should be considered for the screening of microdeletions of Yq involving the AZFc region even in the presence of a varicocele.

Adult↗
PubMed2000

Fragile X syndrome and 22q11.2 microdeletion in the same sibship.

We present a family with an unusual association of two frequent genetic disorders, 22q11.2 microdeletion and fragile X syndrome, originating from the same parent. Our observation confirms the wide intrafamilial clinical variability of the 22q11.2 microdeletion and illustrates the difficulty of the clinical diagnosis for the fragile X syndrome in affected females.

Child, Preschool↗
PubMed2002

[Chromosome Y microdeletions in the pathogenesis of male infertility].

Since over 10 years the Y chromosome has been the subject of interest of geneticists. Until now its role has been proven in in male sex determination and development but the function of the remaining genes located on it is still within the sphere of intense research. Studies for identification of location of sequences responsible for normal course of spermatogenesis process in men have been performed since 1970s. It is believed that the factor responsible for these disorders is the gene conventionally called AZF (azoospermia factor) located probably in the euchromatic part of the long arm in Yq11.23 locus. The incidence of Y microdeletion in infertile males ranges from 1 to 55%, according to various authors. Estimated data demonstrate that about 10-15% of cases of azoospermia and about 5-10% of cases of severe oligospermia are caused by Y chromosome microdeletion.

Chromosome Deletion↗
PubMed2002

AZF microdeletions associated with idiopathic and non-idiopathic cases with cryptorchidism and varicocele.

AIM: To identify submicroscopic interstitial deletions in azoospermia factor (AZF) loci in idiopathic and non-idiopathic cases of male infertility in Indians. METHODS: One hundred and twenty two infertile males with oligozoospermia or azoospermia were included in this study. Semen analysis was done to determine the sperm density, i.e., normospermia (>20 million/mL), oligozoospermia (<20 million/mL) or azoospermia. They were subjected to detailed clinical examination and endocrinological and cytogenetic study. Thirty G-banded metaphases were analyzed in the 122 cases and polymerase chain reaction (PCR) microdeletion analysis was done in 70 cytogenetically normal subjects. For this genomic DNA was extracted using peripheral blood. The STS primers tested in each case were sY84, sY86 (AZFa); sY127, sY134 (AZFb); sY254, sY255 (AZFc). PCR amplifications found to be negative were repeated at least 3 times to confirm the deletion of a given marker. The PCR products were analyzed on a 1.8 % agarose gel. RESULTS: Eight of the 70 cases (11.4 %) showed deletion of at least one of the STS markers. Deletions were detected in cases with known and unknown aetiology with bilateral severe testiculopathy and also in cryptorchid and varicocele subjects. CONCLUSION: AZF microdeletions were seen in both idiopathic and non-idiopathic cases with cryptorchidism and varicocele. The finding of a genetic aetiology in infertile men with varicocele and cryptorchidism suggests the need for molecular screening in non-idiopathic cases.

Adult↗
PubMed2002

[Progress on Y chromosome microdeletions and male infertility].

About 10%-15% of azoospermic and 5%-10% of severely oligozoospermic men with idiopathic infertility have Yq microdeletions which could be transmitted to their male offspring by means of ICSI. We review present studies about Yq microdeletions including incidence, region, correlations between genotype and phenotype, the mechanism of Yq deletions and try to further understand the cause of male infertility as well as provide a new way for diagnosis and therapy.

Chromosome Deletion↗
PubMed2003

[Microdeletion of the azoospermia factor as one of the causes of male infertility].

One of the possible causes of male infertility is microdeletion of the Y chromosome in the Yq11.23 region--named the azoospermia factor. These deletions are associated with azoospermia or severe oligozoospermia. In these cases, testicular histopathological findings comprise a wide spectrum, from total absence of germ cells, through arrest of their maturation to decreased sperm production. Most Y-chromosome microdeletions arise de novo but transmission from the father is also possible, either by the natural way or by assisted reproduction. In relation to the assisted reproduction, the relationship between the Y-deletions and presence of spermatozoa in testis, fertilization capability and embryo quality were examined. Heredity of the deleted Y chromosome is holandric and therefore all sons of males with deletions will carry the same defect and will probably have fertility problems. Another negative influence of deletions on a man's health has not yet been identified.

Chromosomes, Human, Y↗
PubMed2004

[FISH detected 11q23 microdeletion and translocation at the long arm of chromosome 11 in a child with normal karyotypic acute lymphoblastic leukemia].

We report on a 6-year-old girl with acute lymphoblastic leukemia (ALL) with 11q23 microdeletion and translocation at the long arm of chromosome 11, which were detected by fluorescence in situ hybridization (FISH) but not by conventional cytogenetics. She was hospitalized because of fever and generalized bone pain. Results of peripheral blood examination included a WBC of 5,400/microliter with 12% lymphoblasts. Bone marrow studies showed 75% of early pre-B lineage lymphoblasts with L1 morphology. G-banding chromosome analysis demonstrated a normal karyotype. However, FISH using mixed lineage leukemia (MLL) and 11q subtelomere probes demonstrated 11q23 microdeletion and translocation at the long arm of chromosome 11 to an undefined chromosome. MLL rearrangement was not detected by Southern blotting analysis. The patient achieved complete remission 15 days after receiving high-risk group chemotherapy of the Kyoto University Pediatric Hematology/Oncology Study Group and has remained in complete remission for more than 30 months. Since MLL/11q23 abnormalities confer a poor prognosis in childhood ALL, the accurate detection of such abnormalities is of paramount significance in assigning individual cases to risk categories. The findings from the present case and recent literature indicate that the FISH-based approach is complementary to conventional cytogenetics, and should be systematically used in childhood ALL at diagnosis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Molecular study on Y chromosome microdeletions in Egyptian males with idiopathic infertility.

AIM: To determine the frequency of genetic deletions within the azoospermia factors in Egyptian infertile males. METHODS: The Yq microdeletions in 33 infertile males with undetectable chromosomal anomalies were examined by mutiplex polymerase chain reaction (PCR). Deletions were confirmed using single PCR amplifications. RESULTS: Four out of the total 33 (12 %) men had Yq(11) microdeletions, thus supporting the average reported figures in other populations. Three of those 4 cases had single short tandem sequence deletions with discrete histological findings of their testes. Single sY272 deletion within AZFc was associated with Sertoli cell only syndrome, whereas a patient with isolated sY84 deletion within AZFa had immature testicular structure. The remaining case had a large deletion in AZFa-c and short stature. CONCLUSION: The present study supports the hypothesis that the Yq(11) encompasses genetic determinants of stature besides genes controlling spermatogenesis.

Adult↗
PubMed1994

p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions.

Pancreatic adenocarcinoma is a major cause of cancer death, and yet little is known about its molecular pathogenesis. We identified p53 mutations in 19 (70%) of 27 primary pancreatic adenocarcinomas. Most were missense point mutations, and the mutations were distributed primarily within the evolutionarily conserved domains. Transitions predominated over transversions, and many of the transitions were at CpG dinucleotides. Intragenic deletions accounted for 32% of mutations and were associated with decreased survival (P = 0.0016). A review of 1937 published p53 mutations revealed that the occurrence of small (1-2 base pairs) microdeletions varied among different types of human neoplasms and that pancreatic adenocarcinoma had one of the highest frequencies (13% of 47 mutations, P = 0.0036). Many small deletions occurred in iterations of single bases, but this did not fully account for their pattern of distribution, and there was evidence for the involvement of homocopolymer (polypurine:polypyrimidine) tracts. This may represent a more widespread phenomenon, because microdeletions occur in similar sequence patterns in reports of somatic and germ line mutations among genes other than p53.

Adenocarcinoma↗
PubMed1993

De novo microdeletion on an inherited Robertsonian translocation chromosome: a cause for dysmorphism in the apparently balanced translocation carrier.

Robertsonian translocations are usually ascertained through abnormal children, making proposed phenotypic effects of apparently balanced translocations difficult to study in an unbiased way. From molecular genetic studies, though, some apparently balanced rearrangements are now known to be associated with phenotypic abnormalities resulting from uniparental disomy. Molecular explanations for other cases in which abnormality is seen in a balanced translocation carrier are being sought. In the present paper, an infant is described who has retarded growth, developmental delay, gross muscular hypotonia, slender habitus, frontal bossing, micrognathia, hooked nose, abundant wispy hair, and blue sclerae. Cytogenetically, she appeared to be a carrier of a balanced, paternally derived 14;21 Robertsonian translocation. Analysis of DNA polymorphisms showed that she had no paternal allele at the D14S13 locus (14q32). Study of additional DNA markers within 14q32 revealed that her previously undescribed phenotype results from an interstitial microdeletion within 14q32. Fluorescent in situ hybridization was used to show that this microdeletion had occurred de novo on the Robertsonian translocation chromosome. These observations may reactivate old suspicions of a causal association between Robertsonian translocations and de novo rearrangements in offspring; a systematic search for similar subcytogenetic rearrangements in other families, in which there are phenotypically abnormal children with apparently balanced translocations, may be fruitful. The clinical and molecular genetic data presented also define a new contiguous gene syndrome due to interstitial 14q32 deletion.

Abnormalities, Multiple↗
PubMed1996

Y chromosome microdeletions and male subfertility.

Men with azoospermia and severe oligozoospermia have been investigated by molecular probing of the long arm of the Y chromosome. We find microdeletions affecting various parts of the long arm of the Y chromosome in approximately 10% of men with non-obstructive azoospermia and severe oligozoospermia but not in a fertile comparison population. This work needs further confirmation in different countries and different racial groups but it would appear that microdeletions (and presumably genetic defects) are commonly associated with defects of spermatogenesis. These findings have implications for the management of severe male subfertility with in vitro fertilization/intracytoplasmic sperm injection.

Case-Control Studies↗
PubMed1997

Prenatal diagnosis of 22q11 microdeletion.

Microdeletion of 22q11 is responsible for DiGeorge syndrome, velocardiofacial syndrome, congenital conotruncal heart defects, and related disorders. Familial transmission accounts for about 10-20 per cent of cases and most of the parents with deletions are nearly asymptomatic. This phenotypic variability makes it difficult to give appropriate genetic counselling. We report our experience on prenatal diagnosis of 22q11 deletion. We proposed prenatal detection of 22q11 microdeletion in 33 pregnancies. In two instances the parents refused prenatal diagnosis and one pregnancy ended spontaneously before the time of sampling. Fluorescent in situ hybridization (FISH) analysis on cultured amniotic cells with probes mapping in the commonly deleted region was used in the remaining 30 cases. Indications were classified into two groups. The first group included four couples with an abnormal family history of a deleted child and/or a deleted parent. No deletion was found in this group. The second one concerned pregnancies with a prenatally detected heart defect. Among these pregnancies with abnormal ultrasound findings, three deletions were found in the 26 samples tested.

Chromosome Deletion↗
PubMedDate not supplied

DiGeorge syndrome with microdeletion of chromosome 22q11.2: report of one case.

DiGeorge syndrome (DGS) is a congenital anomaly involving developmental defects of the third and fourth pharyngeal pouches. Thymic aplasia or hypoplasia, parathyroid aplasia or hypoplasia, cardiac malformations, and dysmorphic facies are characteristics features. We present a case which had thymic aplasia, hypocalcemia, facial dysmorphism (hypertelorism, low set ears, cleft of soft palate, fish-like mouth and micrognathia) and congenital heart disease (ventricular septal defect, perimembranous type). The T-cell immunologic functions as a percentage of T-cell and phytohemagglutinin stimulation test were within normal range matched with age. Molecular study showed microdeletion of chromosome 22q11.2 by genotype analysis, but chromosome study of high-resolution cytogenetic analysis by G-banding technique was normal. To our knowledge, about 90% of DiGeorge syndrome patients show chromosome abnormalities, most involving chromosome 22 (monosomy of 22q11.2). In the past, most cases were proven by high-resolution cytogenetic analysis or fluorescence in situ hybridization(FISH). We report a case of DGS in Taiwan with microdeletion of chromosome 22q11.2 detected by genotype analysis.

Chromosome Deletion↗
PubMed1999

Microdeletions at chromosome bands 1q32-q41 as a cause of Van der Woude syndrome.

Van der Woude syndrome (VWS) is an autosomal dominant disorder comprising cleft lip and/or cleft palate and lip pits. We reported previously a family whose underlying mutation is a 500-800 kb deletion localized to chromosome bands 1q32-q41 [Sander et al., 1994: Hum Mol Genet 3:576-578]. Along with cleft lip/palate and lip pits, affected relatives exhibit developmental delays, suggesting that the function of a gene nearby may also be disrupted. To further localize the VWS gene we searched for other deletions that cause VWS. An allele loss assay was performed using a novel highly polymorphic marker, D1S3753. From a panel of 37 unrelated individuals, we detected an allele loss in one family, indicating the presence of a deletion. In this family, the phenotype in three generations of affected individuals was confined to the cardinal signs of VWS. Surprisingly, mapping of the new deletion showed that it extended 0.2-1 Mb beyond the proximal breakpoint for the deletion described previously. No deletions were detected in seven cases of popliteal pterygia syndrome, 76 cases of mixed syndromic forms of cleft lip and palate, and 178 cases of nonsyndromic cleft lip and palate. These observations suggest that genetic searches for microdeletions should be routine in screening patients for causes of VWS and may facilitate the positional cloning efforts of the VWS gene and of a nearby gene or genes that may be involved in brain development.

Anodontia↗
PubMed1999

Microdeletion of chromosome sub-band 2q37.3 in two patients with abnormal situs viscerum.

We report on two cases of microdeletion of chromosome sub-band 2q37.3 with abnormal situs viscerum. The first patient had dextrocardia, duodenal and jejunal atresia, and an abdominal hernia. The liver was in the left upper quadrant, stomach in the right upper quadrant. In contrast anema the ascending colon was in the left, and descending colon on the right, with an area of atresia in the mid-jejunum. The second patient had malrotation and malposition of large and small bowel, with most of the bowels positioned above the liver and spleen. There was incomplete rotation of the cecum. The right kidney was malrotated and mal-positioned. The finding of 2q37.3 deletion in both patients implies that a locus or loci involved in the development of normal body situs lies within this chromosome region. Molecular cytogenetic evaluation for a possible 2q37.3 deletion should be considered in patients with abnormal situs viscerum.

Adolescent↗