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PubMed2004

Frontal and caudate alterations in velocardiofacial syndrome (deletion at chromosome 22q11.2).

This study investigated the morphology of the frontal lobe and the caudate nucleus in velocardiofacial syndrome, a neurogenetic disorder caused by a microdeletion at chromosome 22q11.2 and frequently associated with severe psychiatric disturbances. Volumes of the caudate nucleus and subregions of the frontal lobe were compared on magnetic resonance images of 10 children with velocardiofacial syndrome and 10 age- and gender-matched controls. Frontal deep white matter was reduced significantly (by about 23%) in subjects with velocardiofacial syndrome relative to controls. Frontal and prefrontal volumes were also reduced in subjects with velocardiofacial syndrome, although not disproportionately to whole brain volume. The volume of the right caudate nucleus was increased in children with velocardiofacial syndrome. Associations between right caudate and right frontal regions were noted in controls but not in children with velocardiofacial syndrome. These findings suggest frontostriatal dysfunction in children with velocardiofacial syndrome. Insofar as up to 30% of adults with velocardiofacial syndrome (also known as chromosome 22q11 deletion syndrome) develop schizophrenia and frontostriatal dysfunction has been noted in schizophrenia, the findings support the hypothesis that velocardiofacial syndrome might represent a neurodevelopmental model of schizophrenia.

Adolescent↗
PubMed2005

Neurogenic arthrogryposis multiplex congenita and velopharyngeal incompetence associated with chromosome 22q11.2 deletion.

We report a case of neurogenic arthrogryposis multiplex congenita and velopharyngeal incompetence in association with a chromosome 22q11.2 deletion in a 5-month-old boy, the only child of a non-consanguineous couple without relevant antecedents. Specifically, polymerase chain reaction amplification of microsatellite markers revealed a noninherited microdeletion in position D22S306. This phenotype has not been reported previously in association with chromosome 22q11.2 deletions, and these findings raise the possibility that at least some cases of neurogenic arthrogryposis multiplex congenita might be due to genetic defects of this type.

Arthrogryposis↗
PubMed1990

Isolated lissencephaly: report of four patients from two unrelated families.

Lissencephaly is a brain malformation manifested by a smooth cerebral surface and caused by incomplete neuronal migration. Clinical sequellae include minor craniofacial changes (bitemporal hollowing, small jaw), severe mental retardation, and other neurological abnormalities. Patients with classical or type I lissencephaly and its sequellae but no other significant anomalies are classified as having isolated lissencephaly sequence. Possible causes of isolated lissencephaly sequence include ischemia or viral infection during the time of neuronal migration, microdeletion within the Miller-Dieker syndrome critical region in chromosome band 17p13.3, and Mendelian inheritance. The last is based on a report of a single family with three affected children in 1933. We report four patients with isolated lissencephaly sequence from two unrelated families who provide further support for autosomal (or possibly X-linked) recessive inheritance. In the first family, three brothers were affected. In the second, the parents are first cousins.

Brain↗
PubMed1999

Agenesis of the corpus callosum associated with DiGeorge-velocardiofacial syndrome: a case report and review of the literature.

We report a patient with clinical and cytogenetic findings consistent with DiGeorge-velocardiofacial syndrome and agenesis of the corpus callosum. This patient represents the first report of a case of DiGeorge-velocardiofacial syndrome associated with such a central nervous system abnormality. This case, together with previous reports in the literature, suggests that structural brain abnormalities, and in particular abnormalities of the corpus callosum, are part of the complex syndrome associated with the chromosomal microdeletion 22q11.2. We suggest that the diagnosis of DiGeorge-velocardiofacial syndrome be entertained in patients with agenesis of the corpus callosum in the context of other common clinical features of this syndrome.

Abnormalities, Multiple↗
PubMed2005

Molecular Pathogenesis of MDS.

Clonal disorders of hematopoiesis, such as myelodysplastic syndromes (MDS) and myeloproliferative diseases (MPD), affect both hematopoietic stem cells and progenitor cells within the erythroid, platelet and granulocytic lineages and can have devastating consequences in children and adults. The genetic features of these diseases often include clonal, nonrandom chromosomal deletions (e.g., 7q-, 5q-, 20q-, 6q-, 11q- and 13q-) that appear to inactivate tumor suppressor genes required for the normal development of myeloid cells (reviewed in Bench and Fenaux). These putative tumor suppressors have proved to be much more difficult to identify than oncogenes activated by chromosomal translocations, the other major class of chromosomal lesions in MDS and MPD. Although MDS and MPD are almost certainly caused by mutations in stem/progenitor cells, the role of inactivated tumor suppressor genes in this process remains poorly understood. In a small portion of myeloid diseases, mutations have been identified in genes encoding factors known to be required for normal hematopoiesis, such as PU.1, RUNX1, CTNNA1 (alpha-catenin) and c/EBPalpha, and implicating these genes as tumor suppressors. Nonetheless, the identities of most deletion-associated tumor suppressors in these diseases remains elusive, despite complete sequencing of the human genome. The deleted regions detected by cytogenetic methods are generally very large, containing many hundreds of genes, thus making it hard to locate the critical affected gene or genes. It is also unclear whether dysfunctional myelopoiesis results from haploinsufficiency, associated with the deletion of one allele, or from homozygous inactivation due to additional point mutations or microdeletions of the retained wild-type allele. In general MDS have proved surprisingly resistant to conventional treatments. Targeted therapeutic advances in MDS will likely depend on a full comprehension of underlying molecular mechanisms, in particular the tumor suppressor genes lost through clonal, nonrandom chromosomal deletions, such as the 7q- and (del)5q.

Adult↗
PubMed2004

Genetic complementation reveals a novel human congenital disorder of glycosylation of type II, due to inactivation of the Golgi CMP-sialic acid transporter.

We have identified a homozygous G>A substitution in the donor splice site of intron 6 (IVS6 + 1G>A) of the cytidine monophosphate (CMP)-sialic acid transporter gene of Lec2 cells as the mutation responsible for their asialo phenotype. These cells were used in complementation studies to test the activity of the 2 CMP-sialic acid transporter cDNA alleles of a patient devoid of sialyl-Le(x) expression on polymorphonuclear cells. No complementation was obtained with either of the 2 patient alleles, whereas full restoration of the sialylated phenotype was obtained in the Lec2 cells transfected with the corresponding human wild-type transcript. The inactivation of one patient allele by a double microdeletion inducing a premature stop codon at position 327 and a splice mutation of the other allele inducing a 130-base pair (bp) deletion and a premature stop codon at position 684 are proposed to be the causal defects of this disease. A 4-base insertion in intron 6 was found in the mother and is proposed to be responsible for the splice mutation. We conclude that this defect is a new type of congenital disorder of glycosylation (CDG) of type IIf affecting the transport of CMP-sialic acid into the Golgi apparatus.

Alternative Splicing↗
PubMed2001

Gene conversion homogenizes the CMT1A paralogous repeats.

BACKGROUND: Non-allelic homologous recombination between paralogous repeats is increasingly being recognized as a major mechanism causing both pathogenic microdeletions and duplications, and structural polymorphism in the human genome. It has recently been shown empirically that gene conversion can homogenize such repeats, resulting in longer stretches of absolute identity that may increase the rate of non-allelic homologous recombination. RESULTS: Here, a statistical test to detect gene conversion between pairs of non-coding sequences is presented. It is shown that the 24 kb Charcot-Marie-Tooth type 1A paralogous repeats (CMT1A-REPs) exhibit the imprint of gene conversion processes whilst control orthologous sequences do not. In addition, Monte Carlo simulations of the evolutionary divergence of the CMT1A-REPs, incorporating two alternative models for gene conversion, generate repeats that are statistically indistinguishable from the observed repeats. Bounds are placed on the rate of these conversion processes, with central values of 1.3 x 10(-4) and 5.1 x 10(-5) per generation for the alternative models. CONCLUSIONS: This evidence presented here suggests that gene conversion may have played an important role in the evolution of the CMT1A-REP paralogous repeats. The rates of these processes are such that it is probable that homogenized CMT1A-REPs are polymorphic within modern populations. Gene conversion processes are similarly likely to play an important role in the evolution of other segmental duplications and may influence the rate of non-allelic homologous recombination between them.

Journal Article↗
PubMed2004

Molecular analysis using DHPLC of cystic fibrosis: increase of the mutation detection rate among the affected population in Central Italy.

BACKGROUND: Cystic fibrosis (CF) is a multisystem disorder characterised by mutations of the CFTR gene, which encodes for an important component in the coordination of electrolyte movement across of epithelial cell membranes. Symptoms are pulmonary disease, pancreatic exocrine insufficiency, male infertility and elevated sweat concentrations. The CFTR gene has numerous mutations (>1000) and functionally important polymorphisms (>200). Early identification is important to provide appropriate therapeutic interventions, prognostic and genetic counselling and to ensure access to specialised medical services. However, molecular diagnosis by direct mutation screening has proved difficult in certain ethnic groups due to allelic heterogeneity and variable frequency of causative mutations. METHODS: We applied a gene scanning approach using DHPLC system for analysing specifically all CFTR exons and characterise sequence variations in a subgroup of CF Italian patients from the Lazio region (Central Italy) characterised by an extensive allelic heterogeneity. RESULTS: We have identified a total of 36 different mutations representing 88% of the CF chromosomes. Among these are two novel CFTR mutations, including one missense (H199R) and one microdeletion (4167delCTAAGCC). CONCLUSION: Using this approach, we were able to increase our standard power rate of mutation detection of about 11% (77% vs. 88%).

5' Untranslated Regions↗
PubMed2006

Rubinstein-Taybi Syndrome: spectrum of CREBBP mutations in Italian patients.

BACKGROUND: Rubinstein-Taybi Syndrome (RSTS, MIM 180849) is a rare congenital disorder characterized by mental and growth retardation, broad and duplicated distal phalanges of thumbs and halluces, facial dysmorphisms and increased risk of tumors. RSTS is caused by chromosomal rearrangements and point mutations in one copy of the CREB-binding protein gene (CREBBP or CBP) in 16p13.3. To date mutations in CREBBP have been reported in 56.6% of RSTS patients and an average figure of 10% has ascribed to deletions. METHODS: Our study is based on the mutation analysis of CREBBP in 31 Italian RSTS patients using segregation analysis of intragenic microsatellites, BAC FISH and direct sequencing of PCR and RT-PCR fragments. RESULTS: We identified a total of five deletions, two of the entire gene and three, all in a mosaic condition, involving either the 5' or the 3' region. By direct sequencing a total of 14 de novo mutations were identified: 10 truncating (5 frameshift and 5 nonsense), one splice site, and three novel missense mutations. Two of the latter affect the HAT domain, while one maps within the conserved nuclear receptor binding of (aa 1-170) and will probably destroy a Nuclear Localization Signal. Identification of the p.Asn1978Ser in the healthy mother of a patient also carrying a de novo frameshift mutation, questions the pathogenetic significance of the missense change reported as recurrent mutation. Thirteen additional polymorphisms, three as of yet unreported, were also detected. CONCLUSION: A high detection rate (61.3%) of mutations is confirmed by this Italian study which also attests one of the highest microdeletion rate (16%) documented so far.

Adolescent↗
PubMed2005

Non-obstructive azoospermia and maturation arrest with complex translocation 46,XY t(9;13;14)(p22;q21.2;p13) is consistent with the Luciani-Guo hypothesis of latent aberrant autosomal regions and infertility.

OBJECTIVE: To describe clinical and histological features observed in the setting of an unusual complex translocation involving three autosomes (9, 13, and 14) identified in an otherwise healthy male referred for infertility consultation. MATERIALS AND METHODS: The patient was age 30 and no family history was available (adopted). Total azoospermia was confirmed on multiple semen analyses. Peripheral karyotype showed a 46,XY t(9;13;14)(p22:q21.2;p13) genotype; no Y-chromosome microdeletions were identified. Cystic fibrosis screening was negative. Bilateral testis biopsy revealed uniform maturation arrest and peritubular fibrosis. RESULTS: Formal genetic counseling was obtained and the extant literature reviewed with the couple. Given the low probability of obtaining sperm on testicular biopsy, as well as the high risk of any retrieved sperm having an unbalanced genetic rearrangement, the couple elected to proceed with fertility treatment using anonymous donor sperm for insemination. CONCLUSION: Although genes mapped to the Y-chromosome have been established as critical to normal testicular development and spermatogenesis, certain autosomal genes are now also recognized as important in these processes. Here we present clinical evidence to support the Luciani-Guo hypothesis (first advanced in 1984 and refined in 2002), which predicts severe spermatogenic impairment with aberrations involving chromosomes 9, 13, and/or 14, independent of Y-chromosome status. Additional study including fluorescent in situ hybridization and molecular analysis of specific chromosomal regions is needed to characterize more fully the contribution(s) of these autosomes to male testicular development and spermatogenesis.

Journal Article↗
PubMed2004

Chromosomal phenotypes and submicroscopic abnormalities.

The finding, during the last decade, that several common, clinically delineated syndromes are caused by submicroscopic deletions or, more rarely, by duplications, has provided a powerful tool in the annotation of the human genome. Since most microdeletion/microduplication syndromes are defined by a common deleted/duplicated region, abnormal dosage of genes located within these regions can explain the phenotypic similarities among individuals with a specific syndrome. As such, they provide a unique resource towards the genetic dissection of complex phenotypes such as congenital heart defects, mental and growth retardation and abnormal behaviour. In addition, the study of phenotypic differences in individuals with the same microdeletion syndrome may also become a treasury for the identification of modifying factors for complex phenotypes. The molecular analysis of these chromosomal anomalies has led to a growing understanding of their mechanisms of origin. Novel tools to uncover additional submicroscopic chromosomal anomalies at a higher resolution and higher speed, as well as the novel tools at hand for deciphering the modifying factors and epistatic interactors, are 'on the doorstep' and will, besides their obvious diagnostic role, play a pivotal role in the genetic dissection of complex phenotypes.

Animals↗
PubMed2001

Velo-cardio-facial syndrome: a model for understanding the genetics and pathogenesis of schizophrenia.

BACKGROUND: Individuals with velocardio-facial syndrome (VCFS), a genetic disorder associated with microdeletions of chromosome 22q11, are reported to have high rates of psychiatric disorder, particularly schizophrenia. AIMS: To review the evidence for an association between VCFS and schizophrenia: to outline recent neuropsychological, neuroanatomical and genetic studies of individuals with VCFS; and to make recommendations for future work. METHOD: A selective literature review was undertaken. RESULTS: Individuals with VCFS have high rates of psychotic disorders, particularly schizophrenia. In addition, specific neuropsychological and neuroanatomical abnormalities have been reported although it is unclear whether such abnormalities relate to the presence of psychiatric disorder in affected individuals. CONCLUSIONS: Deletion of chromosome 22q11 represents one of the highest known risk factors for the development of schizophrenia. It is likely that haploinsufficiency (reduced gene dosage) of a neurodevelopmental gene or genes mapping to chromosome 22q11, leading to disturbed neuronal migration, underlies susceptibility to psychosis in VCFS.

Abnormalities, Multiple↗
PubMed2002

Comparison of cytogenetic and molecular cytogenetic detection of chromosome abnormalities in 240 consecutive adult patients with acute myeloid leukemia.

PURPOSE: To prospectively compare cytogenetic and molecular cytogenetic analysis for the detection of the most relevant chromosome abnormalities in a large series of patients with acute myeloid leukemia (AML). PATIENTS AND METHODS: Two hundred forty consecutive adult patients with AML entered onto the multicenter treatment trial AML HD93 were studied. Chromosome banding and fluorescence in situ hybridization (FISH) applying a comprehensive set of genomic DNA probes were performed in a single reference laboratory. RESULTS: Two cases of inv(16), three cases of t(11q23), and three cases of t(8;21)var were only detected by molecular cytogenetics. By FISH, aberrations were identified in three cases with normal karyotypes: inv(16), -Y (in a patient with low metaphase yield on chromosome banding) and a 12p microdeletion. Additional aneuploidies, in particular +8q and +11q, were diagnosed by FISH; however, virtually all these aberrations occurred in patients with complex karyotypes or as an additional abnormality in leukemias with an AML-specific translocation. Finally, aberrations were detected by FISH in eight of 14 patients with no assessable metaphases. CONCLUSION: In most cases of AML, conventional cytogenetic study reliably detects chromosomal abnormalities, and this method should not be replaced by FISH. FISH should be used as a complementary method for the detection of more subtle abnormalities, such as inv(16) and t(11q23), in all patients with newly diagnosed AML and for suspected t(8;21)var. Furthermore, molecular cytogenetics using this comprehensive set of DNA probes provides a valuable diagnostic tool for patients with poor chromosome morphology, low or no yields of metaphase cells, or both.

Acute Disease↗
PubMed2003

Functional attenuation of UFD1l, a 22q11.2 deletion syndrome candidate gene, leads to cardiac outflow septation defects in chicken embryos.

Microdeletion of chromosome 22q11.2 is commonly associated with congenital cardiovascular defects that involve development of cranial neural crest cells (NCC) that emigrate through the pharyngeal arches. UFD1l is one of several candidate genes for 22q11.2 deletion syndrome (22q11DS). UFD1l encodes a protein whose yeast counterpart is involved in a ubiquitin-dependent proteolytic degradation pathway; however, the role of UFD1L in NCC development remains unknown. Mouse embryos that lack Ufd1l die before organogenesis. We have therefore studied the function of Ufd1l in the chick system. Chick Ufd1l encoded a 307-amino acid protein that was highly conserved with mouse and human UFD1L. Chick Ufd1l was expressed in the developing neural tube, NCC, and mesenchyme of the head and pharyngeal arch structures, as well as in the conotruncal region (cardiac outflow tract), consistent with the clinical features of 22q11DS. To determine loss-of-function effects of chick Ufd1l in NCC, we infected cardiac NCC with a retrovirus expressing antisense Ufd1l transcripts in chick embryos before their migration. Morphologic analysis of infected embryos at a later developmental stage demonstrated that functional attenuation of chick Ufd1l in cardiac NCC resulted in an increased incidence of conotruncal septation defects. These data suggest that Ufd1l may play a role in cardiac NCC during conotruncal septation.

Adaptor Proteins, Vesicular Transport↗
PubMed2005

Sex differences in cognitive functioning in velocardiofacial syndrome (VCFS).

Sex differences in cognitive functioning were investigated in children with velocardiofacial syndrome (VCFS), a genetic defect caused by a microdeletion on chromosome 22q.11. The study population consisted of six groups: 50 boys with VCFS (M = 11.1, SD = 2.7), 40 girls with VCFS (M = 10.8, SD = 2.5), 13 male siblings of the participant with VCFS (M = 12.3, SD = 1.9), 17 female siblings of the participant with VCFS (M = 12.2, SD = 1.9), and a race- and gender-ratio-matched sample of 28 boy community control participants (M = 10.7, SD =2.4) and 19 girl community control participants (M = 9.2, SD =2.3). Each participant received a psychological assessment including intellectual and academic achievement as well as structural magnetic resonance imaging of his or her brain. Our results indicate that boys with VCFS may be more cognitively affected than girls. In addition, and although cross-sectional in nature, our results document a negative association between age and cognitive functioning in girls with VCFS but not in boys. Sex differences in frontal lobe volume are generally seen in the general population between boys and girls (boys > girls) and across all three samples, this trend emerged. Relative to boys with VCFS, girls with VCFS may be less cognitively affected, although age is negatively associated with cognitive functioning in girls with VCFS but not boys, suggesting that girls with VCFS may fail to maintain this cognitive advantage over boys.

Adolescent↗
PubMed2004

Phenotypic and molecular genetic aspects of pseudohypoparathyroidism type Ib in a Greek kindred: evidence for enhanced uric acid excretion due to parathyroid hormone resistance.

The predominant feature of pseudohypoparathyroidism (PHP) is renal resistance to PTH. Pseudohypoparathyroidism type Ia (PHP-Ia) is caused by maternally inherited heterozygous mutations in the GNAS exons encoding the alpha-subunit of the stimulatory G protein (Gsalpha). Besides PTH resistance, PHP-Ia patients have Albright's hereditary osteodystrophy and often display resistance to additional hormones. Patients with PHP-Ib lack features of Albright's hereditary osteodystrophy, and PTH resistance is associated with loss of methylation at the maternal GNAS exon A/B. Most individuals with the autosomal dominant form of PHP-Ib have a 3-kb microdeletion within STX16 approximately 220 kb upstream of exon A/B. Here we report on the clinical and genetic aspects of a Greek PHP-Ib kindred with four affected members and three obligate carriers, who had the 3-kb deletion within STX16. Symptomatic hypocalcemia was present only in the proband, but PTH was elevated in all members who had inherited the 3-kb deletion maternally. In all affected family members, urinary phosphate excretion was normal, but 1,25-dihydroxyvitamin D levels were diminished. These findings confirm previous data regarding patient to patient variation in disease severity for autosomal dominant PHP-Ib. Furthermore, affected individuals displayed hypouricemia with increased fractional excretion of uric acid, suggesting possible involvement of PTH in the renal handling of this metabolite.

Adult↗
PubMed2006

antiphospholipid antibodies syndrome associated with hyperhomocysteinemia related to MTHFR Gene C677T and A1298C heterozygous mutations in a young man with idiopathic hypoparathyroidism (DiGeorge syndrome).

CONTEXT: Antiphospholipid syndrome (APS, or Hughes' syndrome) is a systemic autoimmune disorder characterized by antiphospholipid antibody positivity, which may lead to arterial and/or venous thrombosis. Hyperhomocysteinemia (HHcy), variously associated with 5,10-methylene tetrahydrofolate reductase (MTHFR) gene point mutations, is also implicated in thromboembolic events. The association of APS and HHcy has already been described but has never been reported in patients with DiGeorge syndrome (DGS), the most common contiguous-gene deletion syndrome (22q11.2) in humans, whose phenotype conversely includes bleeding disorders. DATA ACQUISITION: In this report, we present the case of a 19-yr-old patient with a past medical history of learning disability and obesity affected with idiopathic hypoparathyroidism, metabolic syndrome, and diffuse vasculitis disorders. He was referred to our endocrinology clinic for the management of severe hypocalcemia. At the time of presentation he had been taking antiepileptic drugs for 2 wk and displayed facial dysmorphism (short neck, micrognathia, a small mouth, hypoplastic nasal alae, eye hypertelorism, and low-set simple ears). DGS was suspected and confirmed by both fluorescence in situ hybridization analysis and single nucleotide polymorphism-array analysis, which revealed contiguous gene microdeletion of the chromosome 22q11.2 in the minimal DiGeorge critical region, specifically at the gene locus D22S75 (N25). CONCLUSIONS: APS, revealed by anti-beta-2-glycoprotein and anti-prothrombin antibodies positivity, and moderate HHcy related to heterozygous C677T and A1298C point mutations of the MTHFR gene were identified as a possible cause of thrombotic disorder responsible for the widespread presence of cutaneous and cerebral lesions.

Adult↗
PubMed1998

Clinical review 100: Evaluation and treatment of the infertile couple.

Infertility by itself does not threaten physical health but has a strong impact on the psychological and social well-being of couples. In the last two decades, progress in caring for the infertile couple, in particular progress in the field of assisted reproduction and micromanipulation, has provided significant hope for many couples for whom hope could not have been offered in the past. This is especially true for bilateral tubal disease and for male factor infertility, as nearly all couples with male factor infertility can now undergo either one (or more) IVF or ICSI attempt(s). For couples with other causes of infertility, however, the differences in pregnancy rates often do not reach statistical significance. We must also remember that the total cost incurred for successful delivery for couples with a better chance of successful IVF (i.e. those with tubal disease) increases from approximately $55,000 in American dollars for the first cycle to $73,000 by the sixth cycle. Because of these high costs, many insurers in the United States and many public health systems in Europe do not cover or only partially cover these procedures. Consequently, the availability of IVF and related therapies frequently depends on the couple's ability to pay. Therefore, after having established the correct diagnosis, appropriate treatment should be counseled to the infertile couple keeping in mind the following points: 1) in subfertile couples expectant management should be reasonably counselled if the age of the woman is less than 30 yr and the duration of infertility is less than 36 months, even if oligozoospermia is present; 2) superovulation and timed intercourse seems also to be a reasonable approach in couples with anovulatory, mild/moderate endometriosis, and unexplained infertility; 3) in unexplained infertility, ovarian stimulation (with clomiphene or gonadotropin) and IUI seem to offer some advantage over ovarian stimulation and timed intercourse; 4) IVF can be a firstline approach in tubal sterility and when IUI or IPI cannot be performed because the number of motile sperm is insufficient, but is usually also the final treatment attempt when other methods have failed. The outcome of IVF is negatively influenced mainly by the woman's age; however, the number of deliveries is also generally lower in couples with male factor; 5) ICSI is a further option, which should be limited to couples: a) with very poor semen parameters; b) previous failed fertilization; c) presence of obstructive or nonobstructive azoospermia in which ICSI is combined with sperm extraction from the epididymis or the testis; 6) international register studies demonstrate that the risk of malformation after conventional IVF is not increased; 7) some reports suggest that incidence of congenital major and minor malformations is not increased in children born after ICSI. However, the rate of sex chromosome anomalies in ICSI fetuses has been reported to be approximately 1% in 585 prenatal diagnoses, a frequency increased by a factor of 4 if compared with naturally conceived live-born babies. ICSI bypasses the physiological selection of spermatozoa that occurs at the level of the testis and epididymis, and in the female reproductive tract as well as at the sperm-oocyte interface. As genetic abnormalities are present in a significant percentage of infertile males with impaired spermatogenesis, karyotyping and analysis of the Y chromosome for microdeletions should be carried out in all potential ICSI fathers. Screening for cystic fibrosis gene mutations should also be performed in azoospermia caused by congenital absence of the vas deferens and seminal vesicles. Appropriate genetic counseling should be made available to all ICSI couples whenever a gene or chromosomal anomaly has been identified. With most ARTs the average delivery rate per cycle is approximately 15% and the cumulative delivery rate after several cycles is about 50%. (ABSTRACT TRUNCATED)

Endocrinology↗