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PubMed2026

Evaluation of the efficacy of optical genome mapping in prenatal diagnosis: a retrospective cohort study.

BACKGROUND: Optical genome mapping (OGM) is an emerging cytogenetic method for concurrently detecting structural variants (SVs) and copy number variants (CNVs). However, its clinical application in prenatal diagnosis remains underexplored. METHODS: This study retrospectively evaluated the clinical validity of OGM in prenatal diagnosis by comparing with two routine genetic testing methods: karyotyping and chromosomal microarray analysis (CMA). Both positive and negative cases detected by routine genetic methods were enrolled to evaluate the technical concordance of OGM and its capability to improve diagnostic rate in negative cases. The exclusion criteria were balanced centromeric translocations, mosaic cases with cellular fractions < 20%, and loss of heterozygosity (LOH) < 25 Mb. All samples subjected to OGM testing were anonymized and analyzed blindly. The results from OGM were compared with those from routine genetic testing, and statistical analyses were performed to assess technical concordance and diagnostic rate. RESULTS: Of 217 samples (166 positive samples and 51 negative samples for routine genetic testing), all were successfully tested with OGM, including 2 umbilical cord blood samples, 4 chorionic villi samples, and 211 cultured amniotic fluid samples. Of the 207 reportable chromosomal aberrations from 166 positive samples, the blinded concordance between OGM and CMA, karyotyping, and combination of karyotyping plus CMA was 97.81%, 96.36%, and 97.10%, respectively. OGM missed six aberrations initially, including one LOH, two marker chromosomes, and three microdeletions. However, after reanalysis, its concordance improved to 100% with CMA and 99.03% with karyotyping plus CMA. OGM also diagnosed one additional case of a 3-kb deletion in 51 negative samples, improving the diagnostic rate by 1.96%. Moreover, OGM reclassified the pathogenicity of two microdeletions from pathogenic to uncertain significance in 2 positive cases. Furthermore, OGM clarified the diagnosis suspected by routine genetic testing and improved diagnostic accuracy in some cases. CONCLUSION: As far as we know, this is the largest retrospective study on OGM in prenatal diagnosis, and it includes a broad range of sample types. The results showed that OGM exhibits high concordance among the tested methods and increases the diagnostic rate. Thus, OGM has the potential to become a first-line technique for prenatal diagnosis in the future.

Humans↗

PubMed1998

Velocardiofacial syndrome patients with a heterozygous chromosome 22q11 deletion have giant platelets.

Patients with a microdeletion on chromosome 22q11 demonstrate the clinical picture of the velocardiofacial syndrome. We report on three members of the same family with this microdeletion and velocardiofacial syndrome, all having an increase in platelet size and a mild decrease in platelet number. Their platelet function, however, tested by aggregation and by adherence to collagen in a whole blood perfusion system, was normal. We retrospectively studied the files of 35 other patients with 22q11 deletion and also found that their platelets had an increased size compared with cardiac controls. Moreover, their platelet size correlated negatively with platelet number. Knowing that patients with 22q11 deletion are obligate carriers for a heterozygous glycoprotein Ib beta deletion, these patients can be considered to be heterozygous Bernard-Soulier patients. In addition, a significant increase in platelet size may be a positive predictor for the clinical diagnosis of the velocardiofacial syndrome.

Blood Platelets↗

PubMed2006

Array-based comparative genome hybridization in clinical genetics.

Abnormalities in DNA copy number are frequently found in patients with multiple anomaly syndromes and mental retardation. Array-based comparative genomic hybridization (array-CGH) is a high-resolution, whole-genome technology that improves detection of submicroscopic aberrations underlying these syndromes. Eight patients with mental disability, multiple congenital anomalies, and dysmorphic features were screened for submicroscopic chromosomal imbalances using the GenoSensor Array 300 Chip. Subtelomeric aberrations previously detected by fluorescence in situ hybridization (FISH) analysis were confirmed in two patients, and accurate diagnosis was provided in two previously undiagnosed complex cases. Microdeletions at 15q11.2-q13 in a newborn with hypotonia, cryptorchidism, and hypopigmentation were detected with few discrepancies between the array results and FISH analysis. Contiguous microdeletion of GSCL, HIRA and TBX1 genes at 22q11.2 was identified in a previously undiagnosed boy with an unusual presentation of the VCF/DiGeorge spectrum. In a newborn with aniridia, a borderline false-negative WT1 deletion was observed, most probably because of differences between the size of the genomic deletion and the microarray probe. A false-positive rate of 0.2% was calculated for clone-by-clone analysis, whereas the per patient false-positive rate was 20%. Array-CGH is a powerful tool for the rapid and accurate detection of genetic disorders associated with copy number abnormalities and can significantly improve clinical genetic diagnosis and care.

Abnormalities, Multiple↗

PubMed2004

A case of chromosome 22q11 deletion syndrome diagnosed in a 32-year-old man with hypoparathyroidism.

Congenital hypoparathyroidism typically manifests with hypocalcemia with or without associated characteristic physical findings and is usually diagnosed during the neonatal period. This report describes an African-American male who was diagnosed at age 32 yr to have dysgenesis of the parathyroid glands due to chromosome 22 microdeletion. Symptomatic hypocalcemia did not develop until age 14 yr, a few weeks after initiation of anticonvulsant therapy for generalized tonic-clonic seizures. Because of the timing for onset of symptomatic hypocalcemia, it was presumed that the patient had anticonvulsant-induced hypocalcemia, and he carried that diagnosis for 18 yr. Chromosome 22q11 deletion syndrome was first suspected at age 32 yr, based on the findings of subtle dysmorphic facial features and a history of learning disability in a patient with PTH-deficient hypocalcemia. The diagnosis was confirmed by fluorescence in situ hybridization analysis. This case underscores the variable clinical presentation of this congenital form of hypoparathyroidism. Chromosome 22q11 microdeletions are relatively common, and the diagnosis should be considered even in adults with hypoparathyroidism because of the potential benefit of genetic counseling.

Adult↗

PubMed1997

Y-chromosome deletions in idiopathic severe testiculopathies.

A genetic etiology has been recently proposed for some severe forms of idiopathic male infertility and a region of the Y chromosome long arm (Yq) defined AZF is thought to be critical for the regulation of spermatogenesis. To date, two genes, YRRM and DAZ, have been identified in AZF, but the actual relationship between genotype and phenotype related to AZF deletions is not well characterized. By means of a PCR strategy we typed Yq microdeletions in 16 azoospermic and 22 severely oligozoospermic subjects whose testicular cytological picture (assessed by fine needle aspiration) was that of Sertoli cell-only syndrome and severe hypospermatogenesis, respectively. Microdeletions in AZF were found in 37.5% of azoospermic men and in 22.7% of severely oligozoospermic men, suggesting that very frequently these genetic abnormalities determine a severe quantitative defect in spermatogenesis. Furthermore, DAZ and YRRM do not seem to be the sole genes regulating spermatogenesis, as deletions in these genes were observed in only 6 of the 11 deleted cases. No correlation between the spermatogenic defect and the type of Yq deletion exists. Intracytoplasmic sperm injection performed using spermatozoa of these Y-deleted patients will invariably pass this defect onto their male offspring. Screening for deletion within AZF or at least an informed consent should, therefore, be obtained in all idiopathic infertile male undergoing a program of intracytoplasmic sperm injection of a spermatozoon into the oocyte.

Adult↗

PubMed2004

Terminal 22q deletion syndrome: a newly recognized cause of speech and language disability in the autism spectrum.

OBJECTIVE: Cryptic subtelomeric chromosome rearrangements account for 6% to 10% of idiopathic mental retardation. As cytogenetic and molecular techniques have become more sophisticated, the number of genetic syndromes attributed to these microdeletions has increased. To date, 64 patients have been described in the literature with a more recently recognized microdeletion syndrome, del 22q13.3. The purpose of this study is to present 11 new cases of this recently described syndrome to delineate further the phenotype and to alert the clinician to another genetic condition that should be considered in the differential diagnosis of early hypotonia, delayed speech acquisition, and autistic behavior. METHODS: Eleven patients were evaluated in 3 academic institutions. Clinical features and results of cytogenetic testing were recorded and tabulated. Reasons for referral for genetic evaluation included developmental delay, severe expressive speech and language delay, and dysmorphic features. RESULTS: Age of presentation ranged from 5 months to 46 years. There were 10 female patients and 1 male patient. All of the patients exhibited delayed motor development, some degree of hypotonia, and severe expressive speech and language delay. Dysmorphic facial features included epicanthal folds, large cupped ears, underdeveloped philtrum, loss of cupid's bow, and full supraorbital ridges. Six patients exhibited autistic-like behaviors. Microscopically visible chromosome deletions were observed in 6 patients. In the remainder, the deletion was detected with the use of fluorescence in situ hybridization. CONCLUSIONS: Hypotonia and developmental delay are nonspecific findings observed in many malformation and genetic syndromes. However, in association with severe speech and language delay and autistic-like behavior, this phenotype may be a significant indication to consider the 22q13 deletion syndrome as a potential cause.

Abnormalities, Multiple↗

PubMed2003

Prevalence of Y chromosome deletions in a Brazilian population of nonobstructive azoospermic and severely oligozoospermic men.

We determined the prevalence of Y chromosome deletions in a population of 60 Brazilian nonobstructive azoospermic and severely oligozoospermic men. PCR-based screening of microdeletions was performed on lymphocyte DNA for the presence of 14 sequence-tagged sites (STS) located in the azoospermic factor (AZF) on the Yq chromosome. All STS were amplified efficiently in samples from 12 fertile men tested, but failed to be amplified in samples from fertile women, indicating the specificity of PCR conditions for Yq screening. Overall, 4 of the 60 infertile patients tested (6.7%) exhibited deletion of the Y chromosome, 2 of them being severely oligozoospermic patients (P10 and P32) and 2 azoospermic men (patients P47 and P57). Patients P47 and P57 presented larger deletions in the AZFa, AZFb and AZFc subregions, with apparent loss of Yq material evidenced by karyotype analysis. Patients P10 and P32 presented deletions confined to the AZFc region, involving the DAZ locus. Male relatives of patients P10 and P32 had no Y chromosome deletions and presented a normal karyotype, suggesting a de novo status of the deletions found. Our data add to the growing literature showing that microdeletions of the Y chromosome can be the cause of male idiopathic infertility.

Adult↗

PubMed2003

[A case of Williams syndrome with p47-phox-deficient chronic granulomatous disease].

A 2-month-old boy with a characteristic elfin face was diagnosed as having Williams syndrome by means of specific fluorescence in situ hybridization (FISH) analysis for a chromosomal microdeletion located in 7q11.23. He was suspected to have immunodeficiency because of a persistent enlargement of axillary lymphnodes after immunization with Bacille Calmette-Guerin (BCG) vaccine since 7 month-old of age. The nitroblue tetrazolium test (NBT) and the chemiluminescence test revealed an absence of superoxide production. Western blotting and DNA sequence analysis confirmed the diagnosis of p47-phox-deficient autosomal recessive chronic granulomatous disease (CGD) (A47 degrees CGD). The predominant genetic defect in A47 degrees CGD was a GT deletion at the beginning of exon 2 in neutrophil cytosol factor 1 gene (NCF1) located in 7q11.23. It suggests that CGD in this patient resulted from the hemizygosity of recessive genetic mutation in NCF1 located at 7q11.23 associated with Williams syndrome. In such a disease with the chromosomal microdeletion like Williams syndrome, we should consider a combination with autosomal recessive diseases, the genes of which are located in the hemizygous region.

Granulomatous Disease, Chronic↗

PubMed1999

Y chromosome and male infertility.

Male factor infertility accounts for about half the cases of couple infertility. In more than 60% of cases the origin of reduced testicular function is unknown but they may have an unidentified genetic anomaly. Microdeletions of the long arm of the human Y chromosome are associated with spermatogenic failure and have been used to define three regions of Yq (AZFa, AZFb and AZFc) that are recurrently deleted in infertile males. Several genes have been identified within this region and have been proposed as candidates for infertility. Many of these genes encode proteins involved in post-transcriptional gene expression and therefore could participate in the sperm maturation process. About 10-15% of azoospermic and about 5-10% of severely oligozoospermic men have Yq microdeletions. The deletions are associated with a wide range of histological pictures ranging from Sertoli Cell Only Syndrome (SCOS) to spermatogenic arrest and severe hypospermatogenesis. Assisted reproduction techniques such as in vitro fertilization (IVF) and Intra Cytoplasmic Sperm Injection (ICSI) alone, or in association with testicular sperm retrieval, represent an efficient therapy for these patients. However the potential of these techniques to transmit genetic defects causing male infertility raises the need for a systematic genetic screening and genetic counselling of these patients.

Chromosome Deletion↗

PubMed1990

Ocular findings in Angelman's (happy puppet) syndrome.

Patients with Angelman's syndrome have been reported to have ocular hypopigmentation and a number are now known to have a microdeletion of chromosome 15q 11----13. Detailed ocular examination of eight new cases revealed normal visual acuity and foveal reflexes, but a pigmentary deficiency which is limited to the choroid and iris stroma--both of neural crest origin. Patients with Prader-Willi syndrome have similar ocular features and many have a microdeletion of chromosome 15q 11----13. It is therefore possible that this region may influence neural crest development.

Abnormalities, Multiple↗

PubMed2002

Prenatal diagnosis of tetralogy of Fallot associated with chromosome 22q11 deletion.

Microdeletion of 22q11 is responsible for DiGeorge syndrome, velocardiofacial syndrome, congenital conotruncal heart defects, and related disorders. We report our experiences on prenatal diagnosis by fluorescence in situ hybridization (FISH) for 22q11 deletion in two fetuses with tetralogy of Fallot. Karyotyping and FISH of the parents revealed that one fetus inherited the disease from maternal microdeletion. These findings suggest the importance of performing FISH in pregnancies with prenatally detected tetralogy of Fallot.

Adult↗

PubMed1999

Chromosome 22q11 deletion syndrome: the first three cases reported in Thailand.

The DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes were originally described as separate disorders due to different concerns regarding phenotypes. However, all these disorders have some common clinical manifestations, including congenital heart defect, facial anomaly, and developmental delay. It is now clear that most cases of these syndromes have a common cause resulting from microdeletion of chromosome 22q11. This study reports the first three cases of Thai children presented with developmental delays. All are females who were known cases of congenital heart diseases. Their minor facial anomalies were subtle and not previously recognized as of any syndromes. The chromosome study by fluorescent in situ hybridization technique yielded microdeletion of chromosome 22q11. Without known prevalence in Asian populations, except in Japanese children, further study for chromosome 22q11 deletion syndrome in Asian children with conotruncal heart defects, who also have minor facial anomalies or developmental delays, should be undertaken.

Child↗

PubMed2000

Deletions within the azoospermia factor subregions of the Y chromosome in Hong Kong Chinese men with severe male-factor infertility: controlled clinical study.

OBJECTIVE: To determine the patterns and the prevalence of microdeletions in the azoospermia factor subregions of the Y chromosome in Hong Kong Chinese men with severe male-factor infertility. DESIGN: Controlled clinical study. SETTING: Reproductive centre of a university teaching hospital, Hong Kong. PARTICIPANTS: Fifty-eight men with severe male-factor infertility who participated in the in vitro fertilisation programme from May 1998 through March 1999, and 46 male volunteers with proven fertility. MAIN OUTCOME MEASURES: Polymerase chain reaction analysis of DNA from peripheral blood lymphocytes using six loci spanning the AZFa, AZFb, and AZFc subregions of the Y chromosome. RESULTS. No microdeletions were detected in the fertile controls or in patients with obstructive azoospermia. Deletions within the AZFc subregion were found in 9% (4/44) of men with non-obstructive azoospermia or severe oligospermia. Neither AZFa nor AZFb deletions were detected in any participants. CONCLUSION: Deletions within the azoospermia factor subregions of the Y chromosome are associated with severe male-factor infertility in Hong Kong Chinese men.

Chromosome Deletion↗

PubMedDate not supplied

[Chromosome 22 (22q.11.2) deletion. Etiology of conotruncal heart abnormalities].

Important advances in the diagnosis and treatment of congenital heart disease (CHD) have been made in the past 50 years. Nowadays echocardiogram plays an important role in the diagnosis. This procedure is able to identify a wide range of malformations. Cardiac catheterization is mainly a therapeutic tool, surgery is now performed much earlier because CHDS are diagnosed sometimes before birth or very early in life. All this advances in the diagnosis and treatment of this group of patients, allows them not only a better quality of life but also the possibility of reaching adulthood and having children. The study of the etiology of CHD is a field that has not evolved as fast as the assessment and treatment. Nowadays we have a larger population of adults with CHD. The discovery of a microdeletion of chromosome 22 q11.2 associated with conotruncal cardiac defects, proves a common etiology for clinical phenotypes and conotruncal malformations. In order to identify, which of these patients share the same etiology and presented with this syndrome, we collected a group that shared not only heart defects of the conotruncal type but also specific phenotypic alterations such as broad nasal bridge, nasal dimple, high palate, and digitalization of the first finger among others. The first two patients studied with FISH technique were positive to monosomy of a locus on chromosome 22. Those patients with CHD of conotruncal type should undergo microdeletion testing so genetic counseling can be offered as well as appropriate treatment in areas such as cardiology and developmental psychology.

Child↗

PubMed2000

[22q11.2 chromosome deletion and velo-cardio-facial syndrome in a patient with tetralogy of Fallot].

Velo-cardio-facial syndrome includes the following clinical features: congenital heart anomaly, velo-pharyngeal malformations and dysmorphic facial features. In 80% of the patients microdeletion of the long arm of chromosome 22 can be detected. Many patients with DiGeorge syndrome have the same underlying chromosomal etiology, however the same deletion results in severe dysmorphic features, immune defect, hypocalcaemia and in severe mental retardation. In isolated heart defects deletion can be detected in about 15% of the patients. We report the detection of the microdeletion in a patient with tetralogy of Fallot, minimal dysmorphic facial features and normal psychomotor development. Early diagnosis of 22q11.2 chromosomal deletion is important for genetic counseling and further rehabilitation. We emphasize the importance of genetic screening in patients with isolated congenital heart defects.

Child, Preschool↗

PubMed2001

[A case of Miller-Dieker syndrome associated with satellite on chromosome 17p].

In this report, we describe a one-year-old girl of the Miller-Dieker syndrome(MDS) with lissencephaly, seizures, microcephaly and mental disorders. Cytogenetic studies of this patient confirmed the presence of a 46,XX, 17ps+ chromosome karyotype, but it could not find the microdeletion of 17p13.3. Fluorescence in situ hybridization(FISH) studies confirmed a terminal deletion in the patient using the LIS1 gene probe which mapped to 17p13.3. Further it was also found the satellite on 17p13(17ps) in the patient who was rare associated with MDS. These findings suggest that FISH analysis may be useful method to detect microdeletion of LIS1 gene as 17-specific probe in the investigation of MDS patients.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed2001

The 4P-syndrome. Case description and literature review.

The microdeletion 4p16 has been found in two rare syndromes. Until now they were considered as two different syndromes: the Wolf-Hirschhorn syndrome (WHS) and the Pitt-Rogers-Danks (PRDS) syndrome characterized by a growth retardation before and after birth, microcrania, seizures, characteristic face with thin mouth, maxillary hypoplasia, short and large philtrum, characteristic nose and mental retardation. A case with 4p-16 microdeletion with phenotype characteristics similar to PRDS is reported. The patients described as PRDS are sometimes less seriously affected than patients with WHS. In fact, cases of death are not indicated in the first year of life, internal malformations are less frequent and the face lacks the typical Greek warrior helmet Recent studies have shown that WSS and PRDS are due to the absence of similar if not identical genetic segments and the clinical differences observed could be the outcome of an allele variation on the remaining homologous part.

Abnormalities, Multiple↗

PubMed2001

[Pseudohypoparathyroidism or hypoparathyroidism? A misleading clinical presentation].

We report the case of a 27-year old woman who presented hypocalcemia and hyperphosphoremia during her first pregnancy. Her phenotype was in favor of Albright's hereditary osteodystrophy: short stature, obesity, round face, brachymetacarpy and mental retardation. However, the diagnosis of pseudohypopara thyroidism type Ia was ruled out due to low PTH level (10 pg/ml). The patient's 22q11 microdeletion was suspected and identified because of the association of severe neonatal hypocalcemia, abnormal face and renal malformation in her children. Deletion 22q11 leads to various syndromes, including Di George syndrome, also referred to as CATCH 22 syndrome (Cardiac defect (C), Abnormal face (A), Thymic hypoplasia (T), Cleft palate (C) and Hypocalcemia (H)). Retrospectively, the patient presented with symptoms suggestive of CATCH 22: abnormal face, hypernasal voice suggestive of velopharyngeal insufficiency, mental retardation, recurrent otitis in childhood. It is also noteworthy that there was an idiopathic thrombocytopenic purpura. In conclusion, while the phenotype was suggestive of Albright's hereditary osteodystrophy, the constatation of a low PTH level would cast doubt on this diagnosis. Furthermore, the 22q11 microdeletion should be searched by FISH (Fluorescence In Situ Hybridization) in all patients with hypopara thyroidism of unknown origin, even in the absence of cardiac malformations. Finally, it seems that patients with CATCH 22 would be predisposed to auto-immune disease as a result of thymic dysfunction.

Abnormalities, Multiple↗