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1.
Am J Med Genet A ; 194(4): e63476, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37974505

RESUMEN

Cat Eye Syndrome (CES) is a rare genetic disease caused by the presence of a small supernumerary marker chromosome derived from chromosome 22, which results in a partial tetrasomy of 22p-22q11.21. CES is classically defined by association of iris coloboma, anal atresia, and preauricular tags or pits, with high clinical and genetic heterogeneity. We conducted an international retrospective study of patients carrying genomic gain in the 22q11.21 chromosomal region upstream from LCR22-A identified using FISH, MLPA, and/or array-CGH. We report a cohort of 43 CES cases. We highlight that the clinical triad represents no more than 50% of cases. However, only 16% of CES patients presented with the three signs of the triad and 9% not present any of these three signs. We also highlight the importance of other impairments: cardiac anomalies are one of the major signs of CES (51% of cases), and high frequency of intellectual disability (47%). Ocular motility defects (45%), abdominal malformations (44%), ophthalmologic malformations (35%), and genitourinary tract defects (32%) are other frequent clinical features. We observed that sSMC is the most frequent chromosomal anomaly (91%) and we highlight the high prevalence of mosaic cases (40%) and the unexpectedly high prevalence of parental transmission of sSMC (23%). Most often, the transmitting parent has mild or absent features and carries the mosaic marker at a very low rate (<10%). These data allow us to better delineate the clinical phenotype associated with CES, which must be taken into account in the cytogenetic testing for this syndrome. These findings draw attention to the need for genetic counseling and the risk of recurrence.


Asunto(s)
Aneuploidia , Trastornos de los Cromosomas , Cromosomas Humanos Par 22 , Anomalías del Ojo , Cardiopatías Congénitas , Humanos , Estudios Retrospectivos , Hibridación Fluorescente in Situ , Cromosomas Humanos Par 22/genética , Cardiopatías Congénitas/genética
2.
Int J Mol Sci ; 24(4)2023 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-36835074

RESUMEN

Reciprocal translocation (RT) carriers produce a proportion of unbalanced gametes that expose them to a higher risk of infertility, recurrent miscarriage, and fetus or children with congenital anomalies and developmental delay. To reduce these risks, RT carriers can benefit from prenatal diagnosis (PND) or preimplantation genetic diagnosis (PGD). Sperm fluorescence in situ hybridization (spermFISH) has been used for decades to investigate the sperm meiotic segregation of RT carriers, but a recent report indicates a very low correlation between spermFISH and PGD outcomes, raising the question of the usefulness of spermFISH for these patients. To address this point, we report here the meiotic segregation of 41 RT carriers, the largest cohort reported to date, and conduct a review of the literature to investigate global segregation rates and look for factors that may or may not influence them. We confirm that the involvement of acrocentric chromosomes in the translocation leads to more unbalanced gamete proportions, in contrast to sperm parameters or patient age. In view of the dispersion of balanced sperm rates, we conclude that routine implementation of spermFISH is not beneficial for RT carriers.


Asunto(s)
Análisis de Semen , Semen , Humanos , Embarazo , Femenino , Masculino , Hibridación Fluorescente in Situ , Heterocigoto , Translocación Genética , Espermatozoides , Segregación Cromosómica , Meiosis
3.
J Med Genet ; 59(12): 1234-1240, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36137615

RESUMEN

BACKGROUND: Despite the availability of whole exome (WES) and genome sequencing (WGS), chromosomal microarray (CMA) remains the first-line diagnostic test in most rare disorders diagnostic workup, looking for copy number variations (CNVs), with a diagnostic yield of 10%-20%. The question of the equivalence of CMA and WES in CNV calling is an organisational and economic question, especially when ordering a WGS after a negative CMA and/or WES. METHODS: This study measures the equivalence between CMA and GATK4 exome sequencing depth of coverage method in detecting coding CNVs on a retrospective cohort of 615 unrelated individuals. A prospective detection of WES-CNV on a cohort of 2418 unrelated individuals, including the 615 individuals from the validation cohort, was performed. RESULTS: On the retrospective validation cohort, every CNV detectable by the method (ie, a CNV with at least one exon not in a dark zone) was accurately called (64/64 events). In the prospective cohort, 32 diagnoses were performed among the 2418 individuals with CNVs ranging from 704 bp to aneuploidy. An incidental finding was reported. The overall increase in diagnostic yield was of 1.7%, varying from 1.2% in individuals with multiple congenital anomalies to 1.9% in individuals with chronic kidney failure. CONCLUSION: Combining single-nucleotide variant (SNV) and CNV detection increases the suitability of exome sequencing as a first-tier diagnostic test for suspected rare Mendelian disorders. Before considering the prescription of a WGS after a negative WES, a careful reanalysis with updated CNV calling and SNV annotation should be considered.


Asunto(s)
Variaciones en el Número de Copia de ADN , Exoma , Humanos , Variaciones en el Número de Copia de ADN/genética , Exoma/genética , Estudios Retrospectivos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Estudios Prospectivos
4.
Andrology ; 10(8): 1625-1631, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36026611

RESUMEN

BACKGROUND: The translocation of SRY onto one of the two X chromosomes results in a 46,XX testicular disorder of sex development; this is supposedly because of non-allelic homologous recombination between the protein kinase X gene (PRKX) and the inverted protein kinase Y pseudogene (PRKY). Although 46,XX SRY-positive men are infertile, the literature data indicate that some of these individuals are of short stature (relative to the general population). We sought to determine whether short stature was linked to additional, more complex chromosomal rearrangements. METHODS: Twelve laboratories gathered detailed clinical, anthropomorphic, cytogenetic and genetic data (including chromosome microarray data) on patients with 46,XX SRY-positive male syndrome. RESULTS: SRY was present (suggesting a der(X)t(X;Y)) in 34 of the 38 cases (89.5%). When considering only the 20 patients with chromosome microarray data, we identified several chromosomal rearrangements and breakpoints, especially on the X chromosome. In the five cases for whom the X chromosome breakpoint was located in the pseudoautosomal region, there was partial duplication of the derivate X chromosome. In contrast, in the 15 cases for whom the breakpoint was located downstream of the pseudoautosomal region, part of the derivate X chromosome had been deleted (included the arylsulfatase E [ARSE] gene in 11 patients). For patients with versus without ARSE deletion, the mean height was, respectively, 167.7 ± 4.5 and 173.1 ± 4.0 cm; this difference was not statistically significant (p = 0.1005). CONCLUSION: Although 46,XX SRY-positive male syndromes were mainly because of imbalanced crossover between the X and Y chromosome during meiosis, the breakpoints differed markedly from one patient to another (especially on the X chromosome); this suggests the presence of a replication-based mechanism for recombination between non-homologous sequences. In some patients, the translocation of SRY to the X chromosome was associated with ARSE gene deletion, which might have led to short stature. With a view to explaining this disorder of sex development, whole exome sequencing could be suggested for SRY-negative patients.


Asunto(s)
Trastornos Testiculares del Desarrollo Sexual 46, XX , Arilsulfatasas , Enfermedades Testiculares , Trastornos Testiculares del Desarrollo Sexual 46, XX/genética , Arilsulfatasas/genética , Humanos , Masculino , Proteínas Quinasas , Translocación Genética
5.
Am J Med Genet A ; 179(4): 650-654, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30737907

RESUMEN

The AMME syndrome defined as the combination of Alport syndrome, intellectual disability, midface hypoplasia, and elliptocytosis (AMME) is known to be a contiguous gene syndrome associated with microdeletions in the region Xq22.3q23. Recently, using exome sequencing, missense pathogenic variants in AMMECR1 have been associated with intellectual disability, midface hypoplasia, and elliptocytosis. In these cases, AMMECR1 gene appears to be responsible for most of the clinical features of the AMME syndrome except for Alport syndrome. In this article, we present two unrelated male patients with short stature, mild intellectual disability or neurodevelopmental delay, sensorineural hearing loss, and elliptocytosis harboring small microdeletions identified by array-CGH involving TMEM164 and AMMECR1 genes and SNORD96B small nucleolar RNA for one patient, inherited from their mothers. These original cases further confirm that most specific AMME features are ascribed to AMMECR1 haploinsufficiency. These cases reporting the smallest microdeletions encompassing AMMECR1 gene provide new evidence for involvement of AMMECR1 in the AMME phenotype and permit to discuss a phenotype related to AMMECR1 haploinsufficiency: developmental delay/intellectual deficiency, midface hypoplasia, midline defect, deafness, and short stature.


Asunto(s)
Deleción Cromosómica , Cromosomas Humanos X/genética , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Eliptocitosis Hereditaria/genética , Eliptocitosis Hereditaria/patología , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Proteínas de la Membrana/genética , Nefritis Hereditaria/genética , Nefritis Hereditaria/patología , Proteínas/genética , Niño , Humanos , Masculino , Pronóstico
6.
Clin Genet ; 94(6): 575-580, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30221343

RESUMEN

We report findings from a male fetus of 26 weeks' gestational age with severe isolated intrauterine growth restriction (IUGR). Chromosomal microarray analysis (CMA) on amniotic fluid cells revealed a 1.06-Mb duplication in 19q13.42 inherited from the healthy father. This duplication contains 34 genes including ZNF331, a gene encoding a zinc-finger protein specifically imprinted (paternally expressed) in the placenta. Study of the ZNF331 promoter by methylation-specific-multiplex ligation-dependent probe amplification showed that the duplicated allele was not methylated in the fetus unlike in the father's genome, suggesting both copies of the ZNF331 gene are expressed in the fetus. The anti-ZNF331 immunohistochemical analysis confirmed that ZNF331 was expressed at higher levels in renal and placental tissues from this fetus compared to controls. Interestingly, ZNF331 expression levels in the placenta have previously been reported to inversely correlate with fetal growth parameters. The original observation presented in this report showed that duplication of ZNF331 could be a novel genetic cause of isolated IUGR and underlines the usefulness of CMA to investigate the genetic causes of isolated severe IUGR.


Asunto(s)
Cromosomas Humanos Par 19 , Retardo del Crecimiento Fetal/diagnóstico , Retardo del Crecimiento Fetal/genética , Duplicación de Gen , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Impresión Genómica , Adulto , Biopsia , Proteínas de Unión al ADN/genética , Epigénesis Genética , Femenino , Estudios de Asociación Genética/métodos , Pruebas Genéticas , Humanos , Inmunohistoquímica , Proteínas de Neoplasias/genética , Embarazo , Ultrasonografía Prenatal
7.
Basic Clin Androl ; 28: 5, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29760927

RESUMEN

BACKGROUND: Robertsonian translocations (RobT) are common structural chromosome rearrangements where carriers display a majority of chromosomally balanced spermatozoa from alternate segregation mode. According to some monotony observed in the rates of balanced segregation, is sperm FISH analysis obsolete for RobT carriers? METHODS: Retrospective cohort research study on 23 patients analyzed in our center from 2003 to 2017 and compared to the data of 187 patients in literature from 1983 to 2017.Robertsonian translocation carriers were divided in six groups according to the chromosomes involved in the translocation: 9 patients from our center and 107 from literature carrying 45,XY,der(13;14) karyotype, 3 and 35 patients respectively with 45,XY,der(14;21), 5 and 11 patients respectively with 45,XY,der(13;15), 4 and 7 patients respectively with 45,XY,der(14;15), 1 and 4 patients respectively with 45,XY,der(13;22),and 1 and 10 patients respectively with 45,XY,der(14;22). RESULTS: Alternate segregation mode is predominant in our group of Robertsonian translocation carriers with 73.45% ±8.05 of balanced spermatozoa (min 50.92%; max 89.99%). These results are compliant with the data from literature for all translocations types (p > 0.05) and are consistent among the different types of Robertsonian translocations (p > 0.05) except for der(13;15) that exhibit lower balanced spermatozoa rates (p < 0.05 versus der(13;14), der(14;21), (13;21) and der(15;22)). Normozoospermic patients also display a significantly (p < 0.01) higher rate of balanced sperm cells than patients with abnormal seminograms whatever the defect implied. CONCLUSIONS: According to the discrepancies observed between der(13;15) and all the other Rob T carriers, the differences observed among patients presenting normal and abnormal sperm parameters and the input in genetical counselling, sperm FISH does not seem obsolete for these patients. Moreover, it seems important to collect more data for rare RobT.


CONTEXTE: Le mode de ségrégation chromosomique le plus fréquemment observé chez les patients porteurs de translocation robertsonienne est. un mode équilibré. Les données semblent varier peu selon la translocation analysée. La relative constance des résultats dans le cas de ces translocations robertsoniennes rend elle inutile ces analyses chromosomiques pour ces patients? PATIENTS ET MÉTHODES: Nous avons analysé de façon rétrospective les données spermatiques et de ségrégation méiotique de 23 patients porteurs de translocation robertsonienne, de 2003 à 2017 et comparé les résultats observés à ceux décrits dans la littérature pour 187 patients. RÉSULTATS: Le mode de ségrégation alterne est. prépondérant dans notre série de patients avec 73.45% ±8.05 de spermatozoïdes équilibrés (min 50.92%; max 89.99%). Ces résultats sont en accord avec les données de la littérature, toutes translocations confondues et selon le type de translocation (p > 0.05) sauf pour la translocation der(13;15) où ces taux sont significativement plus faibles (p < 0.05 vs der(13;14), der(14;21), (13;21) et der(15;22)). Nous observons également des taux de spermatozoïdes équilibrés significativement plus élevés chez les patients à spermogramme normal (p < 0.01). CONCLUSIONS: Les différences observées dans les taux d'aneuploïdies entre les translocations der(13;15) et les autres translocations robertsoniennes et entre les porteurs de translocation à spermogramme normal ou altéré, et l'utilité de ces données dans le conseil génétique conduisent à poursuivre l'analyse systématique de la ségrégation méiotique pour les patients porteurs de translocations robertsoniennes et ceci particulièrement pour les translocations rares.

8.
J Med Genet ; 54(7): 502-510, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28270404

RESUMEN

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) represent a significant healthcare burden since it is the primary cause of chronic kidney in children. CNVs represent a recurrent molecular cause of CAKUT but the culprit gene remains often elusive. Our study aimed to define the gene responsible for CAKUT in patients with an 1q23.3q24.1 microdeletion. METHODS: We describe eight patients presenting with CAKUT carrying an 1q23.3q24.1 microdeletion as identified by chromosomal microarray analysis (CMA). Clinical features were collected, especially the renal and urinary tract phenotype, and extrarenal features. We characterised PBX1 expression and localisation in fetal and adult kidneys using quantitative RT-PCR and immunohistochemistry. RESULTS: We defined a 276-kb minimal common region (MCR) that only overlaps with the PBX1 gene. All eight patients presented with syndromic CAKUT. CAKUT were mostly bilateral renal hypoplasia (75%). The most frequent extrarenal symptoms were developmental delay and ear malformations. We demonstrate that PBX1 is strongly expressed in fetal kidneys and brain and expression levels decreased in adult samples. In control fetal kidneys, PBX1 was localised in nuclei of medullary, interstitial and mesenchymal cells, whereas it was present in endothelial cells in adult kidneys. CONCLUSIONS: Our results indicate that PBX1 haploinsufficiency leads to syndromic CAKUT as supported by the Pbx1-null mice model. Correct PBX1 dosage appears to be critical for normal nephrogenesis and seems important for brain development in humans. CMA should be recommended in cases of fetal renal anomalies to improve genetic counselling and pregnancy management.


Asunto(s)
Haploinsuficiencia/genética , Factor de Transcripción 1 de la Leucemia de Células Pre-B/genética , Anomalías Urogenitales/genética , Reflujo Vesicoureteral/genética , Niño , Preescolar , Femenino , Feto/metabolismo , Genoma Humano , Humanos , Lactante , Riñón/anomalías , Riñón/embriología , Riñón/metabolismo , Riñón/patología , Masculino , Síndrome
9.
Eur J Med Genet ; 59(9): 483-7, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27452446

RESUMEN

Array comparative genomic hybridization (aCGH) is now widely adopted as a first-tier clinical diagnostic test for patients with developmental delay (DD)/intellectual disability (ID), autism spectrum disorders, and multiple congenital anomalies. Nevertheless, classic karyotyping still has its impact in diagnosing genetic diseases, particularly mosaic cases. We report on a 30 year old patient with syndromic intellectual disability, a 22q13.2 microdeletion and mosaic trisomy 22. The patient had the following clinical features: intrauterine growth retardation at birth, hypotonia, cryptorchidism, facial asymmetry, enophthalmus, mild prognathism, bifid uvula, hypoplastic upper limb phalanges, DD including speech delay, and ID. Whole genome aCGH showed a de novo 1 Mb interstitial heterozygous deletion in 22q13.2, confirmed by fluorescence in situ hybridization in all cells examined. Moreover, 18% cells had an extra chromosome 22 suggesting a trisomy 22 mosaicism. Almost all 22q13 deletions published so far have been terminal deletions with variable sizes (100 kb to over 9 Mb). Very few cases of interstitial 22q13.2 deletions were reported. In its mosaic form, trisomy 22 is compatible with life, and there are about 20 reports in the literature. It has a variable clinical presentation: growth restriction, dysmorphic features, cardiovascular abnormalities, hemihyperplasia, genitourinary tract anomalies and ID. Neurodevelopmental outcome ranges from normal to severe DD. The patient presents clinical features that are common to both the interstitial 22q13 deletion and the mosaic trisomy 22; characteristics related to the interstitial deletion alone and others explained solely by the mosaic trisomy. Our case points out the role of conventional cytogenetic tools in mosaic cases that could be missed by microarray technology. We therefore suggest the combination of both conventional and molecular karyotyping in the investigation of certain genetic diseases.


Asunto(s)
Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 22 , Discapacidad Intelectual/genética , Trisomía/genética , Disomía Uniparental/genética , Adulto , Aberraciones Cromosómicas , Deleción Cromosómica , Cromosomas Humanos Par 22/genética , Hibridación Genómica Comparativa/métodos , Discapacidades del Desarrollo/genética , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Trastornos del Desarrollo del Lenguaje/genética , Masculino , Mosaicismo
10.
Prenat Diagn ; 36(6): 523-9, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27018091

RESUMEN

OBJECTIVE: Sex chromosome aneuploidies are frequently detected fortuitously in a prenatal diagnosis. Most cases of 47, XXX and 47, XYY syndromes are diagnosed in this context, and parents are thus faced with an unexpected situation. The objective of the present study was to characterize a French cohort of prenatally diagnosed cases of 47, XXX and 47, XYY and to evaluate the termination of pregnancy (TOP) rate before and after France's implementation of multidisciplinary centres for prenatal diagnosis in 1997. METHODS: This retrospective study identified respectively 291 and 175 cases of prenatally diagnosed 47, XXX and 47, XYY between 1976 and 2012. For each case, the indication, maternal age, karyotype and outcome were recorded. RESULTS: Most diagnoses of the two conditions were fortuitous. The occurrence of 47, XXX was associated with advanced maternal age. The overall TOP rate was higher for 47, XXX (22.9%) than for 47, XYY (14.6%), although this difference was not statistically significant. However, the TOP rates fell significantly after 1997 (from 41.1% to 11.8% for 47, XXX and from 25.8% to 6.7% for 47, XYY). CONCLUSION: The TOP rates after prenatal diagnoses of 47, XXX and 47, XYY fell significantly after 1997, following France's implementation of multidisciplinary centres for prenatal diagnosis. © 2016 John Wiley & Sons, Ltd.


Asunto(s)
Aborto Inducido/estadística & datos numéricos , Aborto Espontáneo/epidemiología , Resultado del Embarazo/epidemiología , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/epidemiología , Trastornos de los Cromosomas Sexuales/epidemiología , Cariotipo XYY/epidemiología , Aborto Inducido/tendencias , Adulto , Amniocentesis , Muestra de la Vellosidad Coriónica , Cromosomas Humanos X , Estudios de Cohortes , Femenino , Muerte Fetal , Francia/epidemiología , Humanos , Edad Materna , Embarazo , Diagnóstico Prenatal , Estudios Retrospectivos , Aberraciones Cromosómicas Sexuales , Trastornos de los Cromosomas Sexuales/diagnóstico , Trastornos de los Cromosomas Sexuales/diagnóstico por imagen , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/diagnóstico , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/diagnóstico por imagen , Trisomía/diagnóstico , Cariotipo XYY/diagnóstico , Cariotipo XYY/diagnóstico por imagen
11.
Eur J Hum Genet ; 24(6): 844-51, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26508576

RESUMEN

Although 22q11.2 deletion syndrome (22q11.2DS) is the most recurrent human microdeletion syndrome associated with a highly variable phenotype, little is known about the condition's true incidence and the phenotype at diagnosis. We performed a multicenter, retrospective analysis of postnatally diagnosed patients recruited by members of the Association des Cytogénéticiens de Langue Française (the French-Speaking Cytogeneticists Association). Clinical and cytogenetic data on 749 cases diagnosed between 1995 and 2013 were collected by 31 French cytogenetics laboratories. The most frequent reasons for referral of postnatally diagnosed cases were a congenital heart defect (CHD, 48.6%), facial dysmorphism (49.7%) and developmental delay (40.7%). Since 2007 (the year in which array comparative genomic hybridization (aCGH) was introduced for the routine screening of patients with intellectual disability), almost all cases have been diagnosed using FISH (96.1%). Only 15 cases (all with an atypical phenotype) were diagnosed with aCGH; the deletion size ranged from 745 to 2904 kb. The deletion was inherited in 15.0% of cases and was of maternal origin in 85.5% of the latter. This is the largest yet documented cohort of patients with 22q11.2DS (the most commonly diagnosed microdeletion) from the same population. French cytogenetics laboratories diagnosed at least 108 affected patients (including fetuses) per year from among a national population of ∼66 million. As observed for prenatal diagnoses, CHDs were the most frequently detected malformation in postnatal diagnoses. The most common CHD in postnatal diagnoses was an isolated septal defect.


Asunto(s)
Síndrome de Deleción 22q11/diagnóstico , Pruebas Genéticas/estadística & datos numéricos , Síndrome de Deleción 22q11/epidemiología , Síndrome de Deleción 22q11/genética , Adolescente , Adulto , Niño , Preescolar , Hibridación Genómica Comparativa , Femenino , Francia , Pruebas Genéticas/métodos , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Masculino , Herencia Paterna
12.
Am J Med Genet A ; 167A(8): 1851-8, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25900885

RESUMEN

Disorders of Sex Development (DSD) are a heterogeneous group of disorders affecting gonad and/or genito-urinary tract development and usually the endocrine-reproductive system. A genetic diagnosis is made in only around 20% of these cases. The genetic causes of 46,XX-SRY negative testicular DSD as well as ovotesticular DSD are poorly defined. Duplications involving a region located ∼600 kb upstream of SOX9, a key gene in testis development, were reported in several cases of 46,XX DSD. Recent studies have narrowed this region down to a 78 kb interval that is duplicated or deleted respectively in 46,XX or 46,XY DSD. We identified three phenotypically normal patients presenting with azoospermia and 46,XX testicular DSD. Two brothers carried a 83.8 kb duplication located ∼600 kb upstream of SOX9 that overlapped with the previously reported rearrangements. This duplication refines the minimal region associated with 46,XX-SRY negative DSD to a 40.7-41.9 kb element located ∼600 kb upstream of SOX9. Predicted enhancer elements and evolutionary-conserved binding sites for proteins known to be involved in testis determination are located within this region.


Asunto(s)
Aberraciones Cromosómicas , Trastornos del Desarrollo Sexual/genética , Secuencias Reguladoras de Ácidos Nucleicos , Factor de Transcripción SOX9/genética , Humanos , Masculino
13.
Ann Neurol ; 76(5): 758-64, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25223753

RESUMEN

Synaptic function is central to brain function. Understanding the synapse is aided by studies of patients lacking individual synaptic proteins. Common neurological diseases are genetically complex. Their understanding is likewise simplified by studies of less common monogenic forms. We detail the disease caused by absence of the synaptic protein CNKSR2 in 8 patients ranging from 6 to 62 years old. The disease is characterized by intellectual disability, attention problems, and abrupt lifelong language loss following a brief early childhood epilepsy with continuous spike-waves in sleep. This study describes the phenotype of CNKSR2 deficiency and its involvement in systems underlying common neurological disorders.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Discapacidad Intelectual/metabolismo , Trastornos del Lenguaje/metabolismo , Convulsiones/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Adolescente , Adulto , Edad de Inicio , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/psicología , Niño , Electroencefalografía , Femenino , Heterocigoto , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/psicología , Trastornos del Lenguaje/genética , Trastornos del Lenguaje/psicología , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Linaje , Convulsiones/genética
14.
Am J Med Genet A ; 161A(10): 2504-11, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23949819

RESUMEN

We report on a 22-year-old woman with features of osteogenesis imperfecta (OI), tricho-dento-osseous (TDO) syndrome and intellectual disability. Whole genome oligonucleotide microarray analysis revealed a copy number gain of 3 Mb in 7q32.3-q33 and a loss of 3.4 Mb in 17q21.33-q22. FISH analysis showed that the third copy of 7q32 was inserted into the long arm of one chromosome 17, exactly in the region 17q21.33-q22 that was deleted. The maternal uncle presented with clinical features similar to the proposita and had the same chromosomal anomalies. The mother of the proposita and two other family members were balanced carriers of this rearrangement, interpreted as an interchromosomal reciprocal insertion. Reciprocal insertion/four-break rearrangement is a very rare chromosomal event. The deleted region on chromosome 17 contains 39 genes, including COL1A1 and DLX3 involved in OI and TDO syndrome respectively. The CACNA1G gene on the deleted segment of chromosome 17 may be a good candidate gene to explain the intellectual impairment. © 2013 Wiley Periodicals, Inc.


Asunto(s)
Anomalías Craneofaciales/genética , Hipoplasia del Esmalte Dental/genética , Enfermedades del Cabello/genética , Discapacidad Intelectual/genética , Osteogénesis Imperfecta/genética , Duplicación Cromosómica , Cromosomas Humanos Par 17 , Cromosomas Humanos Par 7 , Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I , Hibridación Genómica Comparativa , Anomalías Craneofaciales/diagnóstico , Hipoplasia del Esmalte Dental/diagnóstico , Femenino , Enfermedades del Cabello/diagnóstico , Proteínas de Homeodominio/genética , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/diagnóstico , Masculino , Persona de Mediana Edad , Mutagénesis Insercional , Osteogénesis Imperfecta/diagnóstico , Linaje , Fenotipo , Eliminación de Secuencia , Síndrome , Factores de Transcripción/genética , Adulto Joven
15.
Hum Reprod ; 27(11): 3337-46, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22888167

RESUMEN

STUDY QUESTION: Can we identify new sequence variants in the aurora kinase C gene (AURKC) of patients with macrozoospermia and establish a genotype-phenotype correlation? SUMMARY ANSWER: We identified a new non-sense mutation, p.Y248*, that represents 13% of all mutant alleles. There was no difference in the phenotype of individuals carrying this new mutation versus the initially described and main mutation c.144delC. WHAT IS KNOWN ALREADY: The absence of a functional AURKC gene causes primary infertility in men by blocking the first meiotic division and leading to the production of tetraploid large-headed spermatozoa. We previously demonstrated that most affected men were of North African origin and carried a homozygous truncating mutation (c.144delC). STUDY DESIGN, SIZE, DURATION: This is a retrospective study carried out on patients consulting for infertility and described as having >5% large-headed spermatozoa. A total of 87 patients are presented here, 43 patients were published previously and 44 are new patients recruited between January 2008 and December 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients consulted for primary infertility in fertility clinics in France (n = 44), Tunisia (n = 30), Morocco (n = 9) or Algeria (n = 4). Sperm analysis was carried out in the recruiting fertility clinics and all molecular analyses were performed at Grenoble teaching hospital. DNA was extracted from blood or saliva and the seven AURKC exons were sequenced. RT-PCR was carried out on transcripts extracted from leukocytes from one patient homozygous for p.Y248*. Microsatellite analysis was performed on all p.Y248* patients to evaluate the age of this new mutation. MAIN RESULTS AND THE ROLE OF CHANCE: We identified a new non-sense mutation, p.Y248*, in 10 unrelated individuals of European (n = 4) and North African origin (n = 6). We show that this new variant represents 13% of all mutant alleles and that the initially described c.144delC variant accounts for almost all of the remaining mutated alleles (85.5%). No mutated transcripts could be detected by RT-PCR suggesting a specific degradation of the mutant transcripts by non-sense mediated mRNA decay. A rare variant located in the 3' untranslated region was found to strictly co-segregate with p.Y248*, demonstrating a founding effect. Microsatellite analysis confirmed this linkage and allowed us to estimate a mutational age of between 925 and 1325 years, predating the c.144delC variant predicted by the same method to have arisen 250-650 years ago. Patients with no identified AURKC mutation (n = 15) have significantly improved parameters in terms of vitality and concentration of normal spermatozoa, and a decreased rate of spermatozoa with a large head and multiple flagella (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Despite adherence to the World Health Organization guidelines, large variations in most characteristic sperm parameters were observed, even for patients with the same homozygous mutation. We believe that is mainly related to inter-laboratory variability in sperm parameter scoring. This prevented us from establishing clear-cut values to indicate a need for molecular analysis of patients with macrozoospermia. WIDER IMPLICATIONS OF THE FINDINGS: This study confirms yet again the importance of AURKC mutations in the aetiology of macrozoospermia. Although a large majority of patients are of North African origin, we have now identified European patients carrying a new non-sense mutation indicating that a diagnosis of absence of a functional AURKC gene should not be ruled out for non-Magrebian individuals. Indirect evidence indicates that AURKC might be playing a role in the meiotic spindle assembly checkpoint (SAC) during meiosis. We postulate that heterozygous men might have a more relaxed SAC leading to a more abundant sperm production and a reproductive advantage. This could be the reason for the rapid accumulation of the two AURKC mutations we observe in North African individuals. STUDY FUNDING/COMPETING INTEREST(S): None of the authors have any competing interest. This work is part of the project 'Identification and Characterization of Genes Involved in Infertility (ICG2I)' funded by the programme GENOPAT 2009 from the French Research Agency (ANR).


Asunto(s)
Infertilidad Masculina/genética , Mutación , Proteínas Serina-Treonina Quinasas/genética , Espermatozoides/anomalías , Adulto , Argelia , Aurora Quinasa C , Aurora Quinasas , Codón sin Sentido , Estudios de Cohortes , Intercambio Genético , Exones , Efecto Fundador , Francia , Estudios de Asociación Genética , Humanos , Infertilidad Masculina/metabolismo , Masculino , Marruecos , Linaje , Proteínas Serina-Treonina Quinasas/metabolismo , Estudios Retrospectivos , Cabeza del Espermatozoide/patología , Espermatozoides/patología , Túnez
16.
Mol Hum Reprod ; 17(12): 762-8, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21733974

RESUMEN

The presence of close to 100% large-headed multi-tailed spermatozoa in the ejaculate has been described as a rare phenotype of male infertility with a very poor prognosis. We demonstrated previously that most cases were caused by a homozygous mutation (c.144delC) in the Aurora Kinase C gene (AURKC) leading to the absence or the production of a non-functional protein. AURKC deficiency in these patients blocked meiosis and resulted in the production of tetraploid spermatozoa unsuitable for fertilization. We describe here the study of two brothers presenting with large-headed spermatozoa. Molecular analysis of the AURKC gene was carried out in two brothers presenting with a typical large-headed spermatozoa phenotype. Both affected brothers were heterozygous for the c.144delC mutation. After complete sequencing of the gene a new heterozygous variant, c.436-2A>G, was identified in both patients. This mutation is located in the acceptor consensus splice site of exon 5. AURKC transcripts were extracted from one of the patient's leukocytes and reverse transcription polymerase chain reaction could be realized showing the presence of a truncated transcript indicating that c.436-2A>G leads to the skipping of exon 5. These results indicate that AURKC molecular analysis of patients with large-headed spermatozoa should not be stopped in the absence of a homozygous recurrent mutation on exon 3 but complete sequence analysis should be performed. This diagnosis is important as the identification of AURKC mutations in patients indicates that all spermatozoa will be chromosomally abnormal and that ICSI should not be attempted.


Asunto(s)
Infertilidad Masculina , Mutación , Proteínas Serina-Treonina Quinasas/genética , Espermatozoides/metabolismo , Aurora Quinasa C , Aurora Quinasas , Secuencia de Bases , Análisis Mutacional de ADN , Exones , Heterocigoto , Humanos , Infertilidad Masculina/diagnóstico , Infertilidad Masculina/genética , Masculino , Meiosis/genética , Datos de Secuencia Molecular , Linaje , Reacción en Cadena de la Polimerasa , Hermanos , Espermatogénesis/genética , Espermatozoides/patología , Túnez
17.
Am J Hum Genet ; 88(3): 351-61, 2011 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-21397064

RESUMEN

An increasing number of couples require medical assistance to achieve a pregnancy, and more than 2% of the births in Western countries now result from assisted reproductive technologies. To identify genetic variants responsible for male infertility, we performed a whole-genome SNP scan on patients presenting with total globozoospermia, a primary infertility phenotype characterized by the presence of 100% round acrosomeless spermatozoa in the ejaculate. This strategy allowed us to identify in most patients (15/20) a 200 kb homozygous deletion encompassing only DPY19L2, which is highly expressed in the testis. Although there was no known function for DPY19L2 in humans, previous work indicated that its ortholog in C. elegans is involved in cell polarity. In man, the DPY19L2 region has been described as a copy-number variant (CNV) found to be duplicated and heterozygously deleted in healthy individuals. We show here that the breakpoints of the deletions are located on a highly homologous 28 kb low copy repeat (LCR) sequence present on each side of DPY19L2, indicating that the identified deletions were probably produced by nonallelic homologous recombination (NAHR) between these two regions. We demonstrate that patients with globozoospermia have a homozygous deletion of DPY19L2, thus indicating that DPY19L2 is necessary in men for sperm head elongation and acrosome formation. A molecular diagnosis can now be proposed to affected men; the presence of the deletion confirms the diagnosis of globozoospermia and assigns a poor prognosis for the success of in vitro fertilization.


Asunto(s)
Acrosoma/patología , Eliminación de Gen , Infertilidad Masculina/genética , Proteínas de la Membrana/genética , Cabeza del Espermatozoide/patología , Acrosoma/metabolismo , Variaciones en el Número de Copia de ADN/genética , Familia , Femenino , Ligamiento Genético , Sitios Genéticos/genética , Homocigoto , Humanos , Jordania , Masculino , Linaje , Cabeza del Espermatozoide/metabolismo
18.
Prenat Diagn ; 30(11): 1072-8, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20842625

RESUMEN

OBJECTIVE: Molecular diagnosis and prenatal care of two pregnant women at risk of transmitting immunodysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome. METHODS: FOXP3 coding sequence and exon boundaries were analyzed in the two consultants and family members. Non-invasive sex determination and specific prenatal diagnosis was realized. RESULTS: Following sequence analysis a new FOXP3 mutation was identified in each consultant. Sex diagnosis realized by amplification of Y sequences from the plasma of the two mothers revealed a male and a female fetus, respectively. Prenatal diagnosis showed that the male fetus was unaffected. The baby is now born and healthy. Subsequent ultrasound examinations confirmed the sex in the second pregnancy but unfortunately led to the diagnosis of a 69,XXX triploidy. The pregnancy was thus interrupted. CONCLUSION: Two new FOXP3 mutations were identified and prenatal diagnosis could be proposed. Due to the rarity of the disease, clinical diagnosis is often considered with delay. Both patients reported here were already pregnant at the beginning of the genetic investigation and one had previously interrupted a male pregnancy for lack of diagnosis. When faced with children with severe refractory diarrhea, clinicians should entertain the possibility of IPEX.


Asunto(s)
Factores de Transcripción Forkhead/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Intestinales/genética , Poliendocrinopatías Autoinmunes/genética , Diagnóstico Prenatal/métodos , Femenino , Factores de Transcripción Forkhead/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Variación Genética , Humanos , Recién Nacido , Enfermedades Intestinales/inmunología , Masculino , Mutación Puntual , Poliendocrinopatías Autoinmunes/inmunología , Embarazo , ARN/química , ARN/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ADN , Síndrome
19.
Hum Mol Genet ; 18(7): 1301-9, 2009 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-19147683

RESUMEN

Infertility concerns a minimum of 70 million couples worldwide. An important proportion of cases is believed to have a genetic component, yet few causal genes have been identified so far. In a previous study, we demonstrated that a homozygous mutation (c.144delC) in the Aurora Kinase C (AURKC) gene led to the production of large-headed polyploid multi-flagellar spermatozoa, a primary infertility phenotype mainly observed in North Africans. We now want to estimate the prevalence of the defect, to improve our understanding of AURKC physiopathology in spermatogenesis and assess its implication in oogenesis. A carrier frequency of 1/50 was established from individuals from the Maghrebian general population, comparable to that of Y-microdeletions, thus far the only known recurrent genetic event altering spermatogenesis. A total of 62 patients were genotyped, all who had a typical phenotype with close to 100% large-headed spermatozoa were homozygously mutated (n = 32), whereas no AURKC mutations were detected in the others. Two homozygous females were identified; both were fertile indicating that AURKC is not indispensible in oogenesis. Previous FISH results had showed a great chromosomal heterogeneity in these patient's spermatozoa. We demonstrate here by flow cytometry that all spermatozoa have in fact a homogeneous 4C DNA content and are thus all blocked before the first meiotic division. Our data thus indicate that a functional AURKC protein is necessary for male meiotic cytokinesis while its absence does not impair oogenesis.


Asunto(s)
Población Negra/genética , Meiosis/genética , Mutación/genética , Proteínas Serina-Treonina Quinasas/genética , África del Norte , Aurora Quinasa C , Aurora Quinasas , Cromatografía Líquida de Alta Presión , Análisis Mutacional de ADN , Exones/genética , Femenino , Fertilidad , Citometría de Flujo , Humanos , Masculino , Modelos Biológicos , Desnaturalización de Ácido Nucleico , Espermatogénesis , Espermatozoides/enzimología , Espermatozoides/patología , Espermatozoides/ultraestructura , Donantes de Tejidos
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