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PubMed2006

[Detection of Y chromosome microdeletions in patients with severe oligozoospermia and azoospermia].

OBJECTIVE: To explore the clinical significance of azoospermia factor (AZF) region deletion. METHODS: Detection of the Y-link sequence tagged sites in AZF region was conducted by means of 2 multiplex polymerase chain reactions among 80 patients with severe oligozoospermia and 63 patients with azoospermia, totally 143. RESULTS: Twenty-one cases of microdeletion were found among the 143 infertile patients with a prevalence of 14.7%. PCR analysis showed that deletion of the portions of Yq in 12 of the 62 idiopathic infertility patients, 3 being with severe oligozoospermia and 9 with azoospermia, and in 9 out of the 81 patients with non-idiopathic infertility. PCR analysis of 40 normal fertile men did not detect any abnormality. The results of the microdeletion showed that 1 patient had a microdeletion in the AZFa region with sY84 and sY86 (1/21, 4.8%), 2 patients presented a large deletion involving sY127 and sY143 from AZFb, and sY254 and sY255 from AZFc (1/21, 9.5%). Two patients had the deletions located in AZFb region (2/21, 9.5%), and 16 patients had a deletion on the AZFc region involving the DAZ (deleted in azoospermia) gene (16/21, 76.2%) Among the 21 infertile men 4 showed a testicular cytologic picture of maturation arrest, 6 patients had severe hypospermatogenesis, and 11 had Sertoli cell-only syndrome. There were not significant differences in location and extent of deletions between the patients with idiopathic infertility and those with non-idiopathic infertility. CONCLUSION: It is recommended to carry out screening of microdeletion of Y chromosome among the patients with idiopathic and non-idiopathic infertility, especially the candidates for intracytoplasmic sperm injection.

Adult↗

PubMed2006

Globozoospermia: Do Y-chromosome microdeletions play a role in this rare spermatogenic disorder?

OBJECTIVE: To explore the possible relationship between Y-chromosome microdeletions and a rare spermatogenic disorder, globozoospermia. STUDY DESIGN: Twelve patients with 100% globozoospermia were evaluated. Each man was questioned about his medical and surgical history and underwent a thorough andrologic examination. Plasma follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone and prolactin levels were measured. Routine sperm analysis and morphology with electron microscopy were done. A set of 17 Y-specific sequence-tagged sites spanning the 3 AZF regions and also RBM1, ZFY, SRY, sY78, CDY, BPY2 and PRY were tested to detect the existence of Y-chromosome microdeletions by polymerase chain reaction. RESULTS: The mean age of the patients was 36 years (range, 27-42). No patient had abnormal blood concentrations of FSH, LH, testosterone or prolactin. Semen analysis revealed normal values for volume (2.2 mL) and concentration (32 x 10(6)/mL) but subnormal values for motility (37%) and progressive motility (24%). On light and electron microscopy, all the spermatozoa were round headed, with abnormal morphologic features. Patients had normal 46,XY karyotyping. No microdeletion of the Y chromosome was detected in any patient. CONCLUSION: Although this study did not find any Y-chromosome microdeletions in patients with globozoospermia, the exact genetic locus resulting in this pathology requires further study.

Acrosome↗

PubMed2006

[Molecular analysis of microdeletions of the Y chromosome in Venezuelan males with idiopathic infertility].

Today infertility is a major health problem affecting about 10-20% of couples. A male factor is assumed to be responsible in about 50% of the infertile couples. The origin of reduced testicular sperm function is unknown in about 60-70% of cases. There are several causes of male infertility such as varicocele, spermatic duct obstruction, and endocrine disorders. Micro-deletions in the Yq are known to represent the pathogenic mechanisms for infertile males. Three different non-overlapping regions designated as AZFa, AZFb, and AZFc are located in interval 5-6 of Yq, and are associated with impaired spermatogenesis in humans. To determine the prevalence of Y chromosomal microdeletions in Venezuelan males with idiopathic infertility, chromosomal, seminal, histological and molecular analyses were carried out in 29 Venezuelan males with idiopathic azoospermia or oligoospermia. Y-microdeletions analyses were performed using a multiplex polymerase chain reaction (PCR)-based technique with 22 sequences-tagged-sites (STSs). One of 29 patients (3.4%) had Yq microdeletions on AZFc. The frequency of AZF microdeletions in Venezuelan patients was similar to other populations with different ethnical or geographical origin.

Azoospermia↗

PubMed1989

The decrease of catalase or esterase D activity in patients with microdeletions of 11p or 13q does not increase their radiosensitivity.

Lymphocyte cultures from patients affected by retinoblastoma (Rb), with or without a microdeletion of chromosome 13, and Wilms tumor (WT), with a microdeletion of chromosome 11p where exposed to gamma-ray radiation during S and G2 phases. Chromatid and chromosome lesions were scored and compared to those observed in controls. No significant differences were detected, neither between patients and controls, nor between patients carrying or not a microdeletion. This lack of difference was unexpected since the genes for catalase and esterase D, also called S-formyl glutathione hydrolase, which are two detoxication enzymes, are deleted in case of microdeletion of 11p and 13q, respectively.

Acatalasia↗

PubMed1995

Chromosome 16 microdeletion in a patient with juvenile neuronal ceroid lipofuscinosis (Batten disease).

The gene that is involved in juvenile neuronal ceroid lipofuscinosis (JNCL), or Batten disease--CLN3--has been localized to 16p12, and the mutation shows a strong association with alleles of microsatellite markers D16S298, D16S299, and D16S288. Recently, haplotype analysis of a Batten patient from a consanguineous relationship indicated homozygosity for a D16S298 null allele. PCR analysis with different primers on DNA from the patient and his family suggests the presence of a cytogenetically undetectable deletion, which was confirmed by Southern blot analysis. The microdeletion is embedded in a region containing chromosome 16-specific repeated sequences. However, putative candidates for CLN3, members of the highly homologous sulfotransferase gene family, which are also present in this region in several copies, were not deleted in the patient. If the microdeletion in this patient is responsible for Batten disease, then we conclude that the sulfotransferase genes are probably not involved in JNCL. By use of markers and probes flanking D16S298, the maximum size of the microdeletion was determined to be approximately 29 kb. The microdeletion may affect the CLN3 gene, which is expected to be in close proximity to D16S298.

Alleles↗

PubMed2025

Spinocerebellar Ataxia 27 A with Episodic Ataxia: Case Series of Fibroblast Growth Factor 14 (FGF14) Microdeletions.

Spinocerebellar ataxia 27 A (SCA27A) is a form of progressive cerebellar ataxia due to pathogenic variants in the Fibroblast Growth Factor 14 (FGF14) gene. The objective of this paper is to characterise the clinical spectrum of SCA27A microdeletions (> 50 bp, <2Mbp), and report two novel cases. Literature searches of PubMed, OMIM and ClinVar were carried out. We identified SCA27A microdeletions in 32 cases across 11 families. The phenotypic presentation is: 75% (24/32) nystagmus, 46% (15/32) ataxia, 21% (7/32) episodic ataxia, 21% (7/32) tremor, 15% (5/32) dysarthria, 34% (11/32) learning disability, 28% (8/32) neuropsychiatric disease. The presentation is variable within and between families. Episodic symptoms, nystagmus, learning disability and neuropsychiatric symptoms occur at an earlier age. Patient 1 represents the first case with a 58 kb FGF14 deletion who presented with a paroxysmal movement disorder. Patient 2 carries a 545 kb deletion and developed episodic ataxia and trigeminal neuralgia, a novel feature not previously described in this cohort. We report two cases of heterozygous FGF14 microdeletions: Patient 1 (58 kb) and Patient 2 (545 kb), expanding the phenotypic spectrum of FGF14 structural variants to 32 cases across 11 families. We review potential mechanism from pre-clinical studies relating FGF14 haploinsufficiency to cerebellar, cognitive, neuropsychiatric symptoms, as well as trigeminal neuralgia. We propose the hypothesis that the episodic symptoms in SCA27A align with the molecular pathology of a channelopathy and propose management strategies based on this insight.

Humans↗

PubMed1997

Familial neurofibromatosis 1 microdeletions: cosegregation with distinct facial phenotype and early onset of cutaneous neurofibromata.

A notable subset of the recent literature on the disorder neurofibromatosis type 1 (NF1) describes patients with NF1, facial anomalies, and other unusual findings. We describe a molecular re-evaluation of two such families reported previously by Kaplan and Rosenblatt [1985], who suggested that their NF1 manifestations, facial phenotype, and other findings could result from a disorder distinct from NF1. Submicroscopic deletions involving the NF1 gene were identified in both families by fluorescent in situ hybridization and analysis of somatic cell hybrids. Affected subjects of the first family were heterozygous for a microdeletion of approximately 2 Mb, which included the entire NF1 gene and flanking contiguous sequences. The family was remarkable for cosegregation of the NF1 microdeletion with facial abnormalities and a pattern of early onset of cutaneous neurofibromata upon transmission from an affected mother to her three affected children. The propositus of the second family carried a deletion that at the least involved NF1 exon 2 through intron 27, which is > 200 kilobases in length. Because all persons in the family were deceased, the size of the deletion could not be determined precisely. Facial anomalies were observed in the propositus and his NF1-affected mother and sister. The data from these families support our hypothesis, which was initially based solely on sporadic deletion cases, that deletion of the entire NF1 gene, or in conjunction with deletion of unknown contiguous genes, causes the facial anomalies and early onset of neurofibromata observed in this subset of NF1 patients. In addition, other features observed in the persons in these families suggest that some NF1 microdeletion patients may be at increased risk for connective tissue abnormalities and/or neoplasms.

Adolescent↗

PubMed2000

Variation in microdeletions of the cyclic AMP-responsive element-binding protein gene at chromosome band 16p13.3 in the Rubinstein-Taybi syndrome.

Most reported microdeletions of the CREB-binding protein (CBP) gene in the Rubinstein-Taybi syndrome (RTS) were detected by fluorescence in situ hybridization (FISH) with a single cosmid probe specific to the 3' region of the gene. In order to test the hypothesis that the rate of microdeletion-positive cases would be greater if the entire gene was evaluated, we performed FISH on 66 patients with an established diagnosis of RTS, using a panel of five cosmids that span the CBP gene. Five of 66 patients had deletions by FISH (9%), consistent with those rates reported in various series that ranged between 3-25%. Among our cases, different deletions were observed; one was deleted for the 5' but not the 3' region of the CBP gene (case 055). Other deletions included a total CBP deletion extending from the 5' through the 3' region (case 017), a deletion of all but the 5' region (cases 006 and 060), and an interstitial deletion in the 3' region (case 028). Fine breakpoint mapping with additional cosmid and yeast artificial chromosome (YAC) constructs was performed on these patients. The findings of a partial 5' deletion and of interstitial deletions of the CBP gene add to the known spectrum of mutations of this gene in RTS and demonstrate the need for evaluation of the entire CBP gene region for deletions rather than only the 3' region in RTS patients. These results further suggest that the true rate of microdeletion across the CBP gene detectable by FISH has yet to be established firmly. No phenotypic differences between partial deletion, complete deletion, and nondeletion patients were observed, supporting a haploinsufficiency model for RSTS.

Chromosomes, Human, Pair 16↗

PubMed1995

Genetic mapping of the cleidocranial dysplasia (CCD) locus on chromosome band 6p21 to include a microdeletion.

Cleidocranial dysplasia (CCD) is a generalized skeletal dysplasia with autosomal dominant inheritance. Recently, the CCD disease locus was localized to 23 [Mundlos et al., 1995] and 17 cM regions [Feldman et al., 1995], of chromosome band 6p21 by linkage studies of seven affected families. Of note, the 23 cM region contained a microdeletion detected in one family at D6S459, an interval that was excluded in the 17 cM overlapping region. Here, linkage of CCD to 6p21 was independently confirmed with a maximal two-point LOD score of Z = 5.12 with marker D6S452 at theta = 0.00. Recombinant events in two affected individuals defined a CCD region of 7 cM from D6S465 to D6S282, which overlapped with the CCD region containing the microdeletion but did not overlap with the 17 cM critical region from D6S282 to D6S291. These results suggest the refined localization of the CCD region to 6 cM spanning markers D6S438 to D6S282, thereby reviving the possibility that the CCD gene lies within the microdeletion at D6S459.

Chromosomes, Human, Pair 6↗

PubMed2001

Phenotype of five patients with Greig syndrome and microdeletion of 7p13.

Here we describe five patients with Greig cephalopolysyndactyly syndrome (GCPS), including one pair of monozygotic twin boys with a de novo microdeletion involving the chromosomal band 7p13, where various clinical manifestations, in addition to GCPS, were recognized. Besides the twin pair, all patients are unrelated. Since there is a considerable lack of well-defined clinical delineation of the few patients with microdeletions involving 7p13 with GCPS described so far, we focus on the symptoms that are not typically related to GCPS, such as moderate psychomotor retardation, seizures, muscle fiber anomalies, cardiac anomalies, hyperglycemia, and hirsutism. Our observations suggest that in all cases of atypical GCPS, the presence of a cytogenetically detectable microdeletion or a submicroscopic deletion of 7p13 should be suspected.

Abnormalities, Multiple↗

PubMed2005

Microdeletion in the SHOX 3' region associated with skeletal phenotypes of Langer mesomelic dysplasia in a 45,X/46,X,r(X) infant and Leri-Weill dyschondrosteosis in her 46,XX mother: implication for the SHOX enhancer.

It is known that SHOX nullizygosity results in Langer mesomelic dysplasia (LMD) and SHOX haploinsufficiency leads to Leri-Weill dyschondrosteosis (LWDC). Here, we report on a microdeletion in the SHOX 3' region identified in a Japanese infant with LMD-compatible skeletal features and a 45,X[191]/46,X,r(X)(p22.3q24)[9] karyotype and in her mother with LWDC-compatible skeletal features and a normal 46,XX karyotype. Physical and auxological examinations revealed mesomelic appearance, ulnarly deviated hands, and borderline micrognathia in the infant, and relatively short forearms and lower legs in the mother. Radiological studies indicated mesomelia, markedly curved radii, hypoplastic ulnas and fibulas, and metaphyseal splaying in the infant, and borderline to mild curvature of the radii, decreased carpal angles, and high-normal triangularization index in the mother. Cytogenetic and molecular studies showed that the ring X chromosome of the infant was missing SHOX and of paternal origin, whereas the cytogenetically normal X chromosomes of the infant and one of the two X chromosomes of the mother, though they retained SHOX with normal coding sequences, had a microdeletion in the SHOX 3' region. The microdeletion started from a position approximately 200 kb from SHOX coding sequences, and spanned 240-350 kb in physical length involving DXYS233. The results, in conjunction with those reported by Flanagan et al. [2002], suggest that a cis-acting enhancer exists in the SHOX 3' region around DXYS233.

3' Flanking Region↗

PubMed2006

Epiphyseal dysplasia and other skeletal anomalies in a patient with the 6p25 microdeletion syndrome.

The 6p25 microdeletion syndrome comprises the Axenfeld-Rieger eye anomaly in association with a characteristic facies, developmental delay, hearing loss, and organ malformations. Skeletal anomalies in the form of hemivertebrae, clubfeet, and other positional joint anomalies have also been described in some patients. We report on a patient with a 2.2-2.4 Mb terminal microdeletion of the short arm of chromosome 6 who in addition had abnormalities of the proximal femoral and humeral epiphyses. We suggest that an epiphyseal dysplasia may be an additional clinical component of the 6p25 microdeletion syndrome.

Abnormalities, Multiple↗

PubMed2006

Distal 4p microdeletion in a case of Wolf-Hirschhorn syndrome with congenital diaphragmatic hernia.

BACKGROUND: Wolf-Hirschhorn syndrome (WHS) is a well-known genetic condition characterized by typical facial anomalies, midline defects, skeletal anomalies, prenatal and postnatal growth retardation, hypotonia, mental retardation, and seizures. Affected patients with a microdeletion on distal 4p present a milder phenotype that lacks congenital malformations. WHS is rarely associated with congenital diaphragmatic hernia (CDH), and only 8 cases are reported in the literature. In almost all cases of CDH and WHS a large deletion of the short arm of chromosome 4 is present. CASE: A microdeletion of 2.6 Mb on distal 4p associated with CDH and multiple congenital malformations (i.e., cleft palate) is reported for the first time. CONCLUSIONS: Such a microdeletion should prompt a molecular study for WHS when in a fetus/newborn with CDH the association with cleft lip/palate and typical facial appearance (flat facial profile, hypertelorism) is found.

Abnormalities, Multiple↗

PubMed2005

Homozygous microdeletion of chromosome 4q11-q12 causes severe limb-girdle muscular dystrophy type 2E with joint hyperlaxity and contractures.

Microdeletion syndromes are commonly transmitted as dominant traits and are frequently associated with variably expressed pleiotropic phenotypes. Nonlethal homozygous microdeletions, on the other hand, are very rare. Here, we delineate the fifth and so far largest homozygous microdeletion in nonmalignancies of approximately 400 kb on chromosome 4q11-q12 in a large consanguineous East-Anatolian family with six affected patients. The deleted region contains the beta-sarcoglycan gene (SGCB), the predicted gene SPATA18 (spermatogenesis associated 18 homolog) and several expressed sequence tags. Patients presented with a severe and progressive Duchenne-like muscular dystrophy phenotype, a combination of hyperlaxity and joint contractures, chest pain, palpitations, and dyspnea.

Adolescent↗

PubMed2003

Idiopathic cases of male infertility from a region in India show low incidence of Y-chromosome microdeletion.

Chromosomal and Y-chromosomal microdeletion analysis has been done in cases of idiopathic infertility with the objective of evaluating the frequency of chromosomal and molecular anomaly as the causal factor of infertility. Barring a few cases of Klinefelter syndrome (XXY or XY/XXY mosaics), no chromosomal anomaly was encountered. Y-microdeletion was analysed by PCR-screening of STSs from different regions of the AZF (AZFa, AZFb, AZFc) on the long arm of the Y, as well as by using DNA probes of the genes RBM, DAZ (Yq), DAZLA (an autosomal homologue of DAZ) and SRY (Yp; sex determining gene). Out of 177 cases examined, 9 (azoospermia - 8 and oligoasthenospermia - 1) showed partial deletion of AZF. The size of deletion varied among patients but AZFc was either totally or partially removed in all of them. In contrast, no deletion was detected in AZFa. Testis biopsy done on a limited number of cases (50) showed diverse stages of spermatogenic arrest with no specific correlation with the genotype. The frequency of Y-chromosome microdeletion in our samples (approximately 5%) is much lower than the frequency (approximately 10%) reported globally and the two previous reports from India. We contend that the frequency may be affected by population structures in different geographical regions.

Biopsy↗

PubMed2006

Chromosome 22 microdeletion by F.I.S.H. in isolated congenital heart disease.

OBJECTIVE: To analyze the frequency of del22q11.2 in non-syndromic CHDs using classical cytogenetics and Fluorescence In Situ Hybridization (FISH) technique in Indian population. METHODS: 105 prospective cases which included 6 families with isolated, non-syndromic cardiac defects were analyzed clinically by a cardiologist and a geneticist. The cases were then subjected to karyotypic (classical cytogenetics) as well as FISH analysis. The efficacy of FISH technique was compared with inference drawn from classical cytogenetics. RESULTS: Karyotypic analysis of all the 105 patients revealed a normal chromosomal complement. Microdeletion 22q11.2 was observed in six patients (5.71%) by FISH studies. FISH studies were also performed on the parents of these six patients who revealed a normal chromosome 22. No correlation was found between clinical features (mild or unspecific) with 22q11.2 microdeletion. CONCLUSION: The testing for microdeletion 22q11.2 in isolated non-syndromic patients using FISH technique is mandatory even when mild/unspecific extracardiac abnormalities are seen in the patients.

Adolescent↗

PubMed2000

Y-chromosomal DNA haplotypes in infertile European males carrying Y-microdeletions.

We have determined Y-chromosomal DNA haplotypes in 73 infertile European males carrying Y microdeletions and compared them with the haplotypes of 299 infertile males lacking microdeletions. Chromosomes were typed with a set of 11 binary Y markers, which identified 8 haplogroups in the sample. Haplogroup frequencies were compared between 3 microdeletion classes and the non-deleted infertile males. Deletions arise on many different haplotypic backgrounds. No statistically significant differences in frequency were seen, although the small number of AZFa deletions lay predominantly on one branch of the Y haplotype tree.

DNA↗

PubMedDate not supplied

Spontaneous transmission from a father to his son of a Y chromosome microdeletion involving the deleted in azoospermia (DAZ) gene.

Microdeletions of the so-called azoospermia factor (AZF) locus of the Y chromosome long arm (Yq) have been recognized as an etiological factor of severe oligozoospermia or azoospermia. Because of this, patients affected are generally infertile unless assisted reproductive techniques are used. We report the case of an oligozoospermic patient (proband) who inherited an extensive Yq microdeletion from his father through a spontaneous pregnancy. Leukocyte DNA was extracted using a commercially available kit. A total of 22 pairs of sequence-tagged site (STSs) based primers, spanning the entire AZF region, were used for the screening. Both the proband and his father carried a Yq microdeletion of the most distal AZF subregion (AZFc) where the deleted in azoospermia (DAZ) gene is located. The proband's father was a sixty-nine-yr-old man who had 3 other children, 2 females and 1 male. This case adds further evidence that the deletion of the DAZ gene is associated with different phenotypic expressions, including normal fertility.

Adult↗