Should cell-free DNA testing be used in pregnancy with increased fetal nuchal translucency?

OBJECTIVE: To assess the frequency of atypical chromosomal and submicroscopic anomalies, as well as fetal structural abnormalities, observed on first-trimester ultrasound scan in fetuses with nuchal translucency (NT) thickness > 99th centile, in order to evaluate the suitability of using standard cell-free DNA (cfDNA) testing as the sole screening test in these pregnancies. METHODS: This was a retrospective cohort study of 226 fetuses with NT > 99th centile at 11-14 weeks' gestation, between January 2013 and December 2017, in a clinical setting in which greater than 95% of pregnant women receive first-trimester combined screening. All patients underwent genetic testing by means of quantitative fluorescence polymerase chain reaction and chromosomal microarray analysis, mainly in chorionic villus samples. We assessed the theoretical yield of two cfDNA testing models, targeted cfDNA (chromosomes 21, 18 and 13) and extended cfDNA (chromosomes 21, 18, 13 and sex chromosomes), and compared it with that of cytogenetic testing and ultrasound assessment in the first and second or third trimesters. RESULTS: In the 226 fetuses analyzed, cytogenetic testing revealed 84 (37%) anomalies, including 68 typical aneuploidies (involving chromosomes 13, 18 or 21), six sex chromosome aneuploidies (four cases of monosomy X and two of trisomy X), three clinically relevant atypical chromosomal anomalies (one trisomy 22, one trisomy 21 mosaicism and one unbalanced translocation), five submicroscopic pathogenic variants and two cases with Noonan syndrome. Targeted and extended cfDNA testing would miss at least 12% (10/84) and 19% (16/84), respectively, of genetic anomalies, accounting for 4.4% and 7.1% of the fetuses with an increased NT, respectively. Finally, of the 142 fetuses with no identified genetic anomaly, a major fetal malformation was observed in 15 (10.6%) fetuses at the early anomaly scan, and in 19 (13.4%) in the second or third trimester. CONCLUSIONS: cfDNA does not appear to be the appropriate genetic test in fetuses with NT > 99th centile, given that it would miss 12-19% of genetic anomalies in this group. Additionally, first-trimester ultrasound will identify a major structural abnormality in 11% of the fetuses with NT > 99th centile and no genetic anomaly. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Spectrum of clinical heterogeneity of ß-tubulin TUBB5 gene mutations.

Microcephaly is a rare condition in which the occipitofrontal circumference in a child is more than two standard deviations below the mean of children of the same age and gender. It is mainly caused by genetic abnormalities that interfere with the growth of the cerebral cortex during early months of fetal development. We present a case of a 12 years old patient with microcephaly. To identify a possible genetic origin of the phenotype, we performed array CGH and exome sequencing in the patient. Exome sequencing revealed the presence of a de novo missense mutation in the TUBB5 gene (E401K). Mutations in the TUBB5 are mainly responsible for microcephaly but the clinical spectrum is wide, from patients with severe developmental delay, and the presence of different brain malformations, to patients with only slightly cognitive impairment and normal motor development. Our patient shows a milder phenotype than other patients carrying the same mutation. These differences in the clinical features suggest that other factors, presumably genetic or epigenetic, could be modulating clinical expressivity of TUBB5. It is therefore evident that more functional studies are needed to understand the pathology that underlies the clinical spectrum of tubulin associated disease states.

Clinical implication of FMR1 intermediate alleles in a Spanish population.

FMR1 premutation carriers (55-200 CGGs) are at risk of developing Fragile X-associated primary ovarian insufficiency as well as Fragile X-associated tremor/ataxia syndrome. FMR1 premutation alleles are also associated with a variety of disorders, including psychiatric, developmental, and neurological problems. However, there is a major concern regarding clinical implications of smaller CGG expansions known as intermediate alleles (IA) or gray zone alleles (45-54 CGG). Although several studies have hypothesized that IA may be involved in the etiology of FMR1 premutation associated phenotypes, this association still remains unclear. The aim of this study was to provide new data on the clinical implications of IA. We reviewed a total of 17 011 individuals: 1142 with primary ovarian insufficiency, 478 with movement disorders, 14 006 with neurodevelopmental disorders and 1385 controls. Similar IA frequencies were detected in all the cases and controls (cases 1.20% vs controls 1.39%, P = .427). When comparing the allelic frequencies of IA ≥ 50CGGs, a greater, albeit not statistically significant, number of alleles were detected in all the cohorts of patients. Therefore, IA below 50 CGGs should not be considered as risk factors for FMR1 premutation-associated phenotypes, at least in our population. However, the clinical implication of IA ≥ 50CGGs remains to be further elucidated.

Fragile X syndrome: An overview and update of the FMR1 gene.

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and the leading form of the monogenic cause of autism. Fragile X mental retardation type 1 (FMR1) gene premutation is the first single-gene cause of primary ovarian failure (Fragile X-associated primary ovarian insufficiency [FXPOI]) and one of the most common causes of ataxia (fragile X-associated tremor/ataxia syndrome [FXTAS]), multiple additional phenotypes such as fibromyalgia, hypothyroidism, migraine headaches, sleep disturbances, sleep apnea, restless legs syndrome, central pain syndrome, neuropathy and neuropsychiatric alterations has been described. Clinical involvement in men and women carrying the FMR1 premutation currently constitutes a real health problem in the society that should be taken into account. It is important to highlight that while in FXS there is a loss-of-function of the FMR1 gene, in premutation associated disorders there is a gain of FMR1 mRNA function. To date, the tremendous progress achieved in the understanding of the pathophysiology of FXS, has led to the development of several targeted therapies aimed at preventing or improving the neurological manifestations of the disease. This review is an update of the diseases associated with the FMR1 gene.

Added value of chromosomal microarray analysis over karyotyping in early pregnancy loss: systematic review and meta-analysis.

OBJECTIVE: To estimate the increased test success rate and incremental yield of chromosomal microarray analysis (CMA) over conventional karyotyping in detection of pathogenic copy number variants (CNVs) and variants of unknown significance (VOUS) in early pregnancy loss. METHOD: This was a systematic review conducted in accordance with PRISMA criteria. All articles identified in PubMed, Ovid MEDLINE and Web of Science, between January 2000 and April 2017, that described CNVs in early pregnancy losses (up to 20 weeks) were included. Risk differences were pooled to estimate the incremental yield of CMA over karyotyping overall, and after stratification. In addition, test success rate, defined as the proportion of informative results, was compared in series in which CMA and karyotyping were performed concurrently. RESULTS: Twenty-three studies, reporting on 5507 pregnancy losses up to 20 weeks with full data available, met the inclusion criteria for analysis. In the series in which CMA and karyotyping were performed concurrently, CMA showed a significant improvement in success rate, providing informative results in 95% (95% CI, 94-96%) of cases compared with karyotyping in which informative results were provided in 68% (95% CI, 66-70%) of cases. Combined data from reviewed studies revealed that incremental yields of CMA over karyotyping were 2% (95% CI, 1-2%) for pathogenic CNVs and 4% (95% CI, 3-6%) for VOUS. The most common pathogenic CNVs reported were 22q11.21 and 1p36.33 deletion. CONCLUSION: In comparison with conventional karyotyping, CMA provides a significant increase in test success rate and incremental diagnostic yield in early pregnancy loss. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Social anxiety and autism spectrum traits among adult FMR1 premutation carriers.

Behavioral symptoms and traits have been proposed as early markers in neurodegenerative diseases. The aim of this study was to evaluate social anxiety and autism in FMR1 premutation carriers using the Social Phobia Inventory (SPIN) and the Autism-Spectrum Quotient (AQ) questionnaires. Fifty-nine premutation carriers were compared with 50 controls. The SPIN test showed statistically significant differences between female but not male carriers. The AQ questionnaire found statistically significant differences between premutation carriers and controls in the total AQ as well as in the social skills and attention switching subdomains. A gender effect was only observed for the social skills subdomain. Spearman's correlation analysis revealed a moderately positive correlation with the total AQ scores as well as the social skills and communication subdomains. Our results show that fragile X-associated tremor/ataxia syndrome (FXTAS) patients have higher AQ scores. Moreover, this is the first study to find statistically significant differences between FXTAS and no-FXTAS premutation carriers in the communication and the imagination subdomains, suggesting that FXTAS patients present a broader autistic phenotype than premutation carriers without FXTAS. Based on our results, a wide range of behavioral/psychiatric traits should be included within the broader phenotypic presentation of individuals with the FMR1 premutation.

Impaired Mitochondrial Function and Dynamics in the Pathogenesis of FXTAS.

Mitochondrial involvement plays an important role in neurodegenerative diseases. At least one-third of adult carriers of a FMR1 premutation (55-200 CGG repeats) are at risk of presenting an adult-onset neurodegenerative disorder known as fragile X-associated tremor/ataxia syndrome (FXTAS). In an attempt to provide new insights into the mechanisms involved in the pathogenesis of FXTAS, we characterized mitochondrial function and dynamics by the assessment of oxidative respiratory chain function, mitochondrial content, oxidative stress levels, and mitochondrial network complexity. Regarding mitochondrial function, we found that mitochondrial respiratory capacity is compromised in skin fibroblasts whereas in blood, no differences were observed between the FXTAS and control groups. Furthermore, fibroblasts from FXTAS patients presented altered mitochondrial architecture, with more circular and less interconnected mitochondria being observed. Mitochondrial function and dynamics deregulation and characteristic of neurological disorders are present in FXTAS patients. These features might be limiting temporal and spatial bioenergetics cells supply and thus contributing to disease pathogenesis.

Deregulation of key signaling pathways involved in oocyte maturation in FMR1 premutation carriers with Fragile X-associated primary ovarian insufficiency.

FMR1 premutation female carriers are at risk for Fragile X-associated primary ovarian insufficiency (FXPOI). Insights from knock-in mouse model have recently demonstrated that FXPOI is due to an increased rate of follicle depletion or an impaired development of the growing follicles. Molecular mechanisms responsible for this reduced viability are still unknown. In an attempt to provide new data on the mechanisms that lead to FXPOI, we report the first investigation involving transcription profiling of total blood from FMR1 premutation female carriers with and without FXPOI. A total of 16 unrelated female individuals (6 FMR1 premutated females with FXPOI; 6 FMR1 premutated females without FXPOI; and 4 no-FXPOI females) were studied by whole human genome oligonucleotide microarray (Agilent Technologies). Fold change analysis did not show any genes with significant differential gene expression. However, functional profiling by gene set analysis showed large number of statistically significant deregulated GO annotations as well as numerous KEGG pathways in FXPOI females. These results suggest that the impairment of fertility in these females might be due to a generalized deregulation of key signaling pathways involved in oocyte maturation. In particular, the vasoendotelial growth factor signaling, the inositol phosphate metabolism, the cell cycle, and the MAPK signaling pathways were found to be down-regulated in FXPOI females. Furthermore, a high statistical enrichment of biological processes involved in cell death and survival were found deregulated among FXPOI females. Our results provide new strategic approaches to further investigate the molecular mechanisms and potential therapeutic targets for FXPOI not focused in a single gene but rather in the set of genes involved in these pathways.

MicroRNA expression profiling in blood from fragile X-associated tremor/ataxia syndrome patients.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with FMR1 gene premutation alleles (55-200 CGG repeats). Fragile X-associated tremor/ataxia syndrome clinical core features include action tremor, gait ataxia, cognitive deficits progressing to dementia, and frequently parkinsonism. Although the pathogenic molecular mechanism of FXTAS is not completely understood, the restriction of the phenotype to the FMR1 premutation range has given rise to a model based on a RNA toxic gain-of-function. Since the identification of the first microRNAs (miRNAs) and their role in normal development, several studies have associated them with neurodegenerative diseases such as Parkinson, Alzheimer and Huntington diseases, suggesting that they play a key role in brain development, as well as in its morphogenesis. Herein, we present the characterization of miRNA expression profiles in FXTAS male patients using deep sequencing-based technologies and microarray technology. Deep sequencing analysis evidenced 83 miRNAs that were significantly deregulated whereas microarray analysis showed 31. When comparing these results, 14 miRNAs were found deregulated in FXTAS patients. MiR-424 and miR-574-3p showed significant fold change adjusted P-values in both platforms in FXTAS patients. MiR-424 has been founded substantially and specifically enriched in human cerebral cortical white matter of Alzheimer disease patients, which, together with cerebral atrophy, is a prominent imaging finding in individuals with FXTAS. The study provides the first systematic evidence of differential miRNA expression changes in FXTAS blood samples. Although further studies are necessary to better characterize the miRNA function in FXTAS disorder, our results suggest that they might contribute to its pathogenesis.

Motor and mental dysfunction in mother-daughter transmitted FXTAS.

OBJECTIVES: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neuropsychiatric degenerative disorder that occurs predominantly in male FMR1 premutation carriers. Recently, a broader FXTAS spectrum that, besides the core features of tremor and gait ataxia, also includes neuropsychiatric symptoms and neuropathy as further clinically relevant symptoms has been described among females. Herein 2 fragile X syndrome families with a mother-daughter FXTAS transmission are described in detail in order to shed more light on the female FXTAS phenotype. METHODS: Molecular characterization included CGG repeat length, X-chromosome inactivation pattern determination, as well as FMR1 mRNA and FMRP levels quantification. Neuroradiologic examination was performed by 3-T MRI. Neuropsychological assessment included global cognitive, attention, and executive prefrontal functions, verbal fluencies, verbal memory, and visuospatial perception. RESULTS: Molecular, neurologic, neuropsychiatric, psychological, cognitive, and neuroradiologic features description of 2 fragile X syndrome families with a mother-daughter FXTAS transmission in which dementia is present in both mothers. CONCLUSIONS: Although it is not yet clear to what extent FXTAS shortens lifespan, our findings show that FXTAS progresses from mild tremor and/or ataxia to disabling motor and cognitive impairment, compromising the patients' quality of life. Furthermore, our results show that FXTAS in women can also develop as a multisystem neurodegenerative disorder with central and peripheral nervous system involvement, and both motor and mental disturbances.

Estudio de reordenamientos subteloméricos en 300 pacientes con retraso mental y anomalías congénitas múltiples: caracterización clínica y molecular / A study of subtelomeric rearrangements in 300 patients with mental retardation and multiple congenital

Introducción. El estudio del retraso mental es uno de los campos más complejos de la genética humana debido a la alta heterogeneidad clínica y genética que presenta. De ahí que actualmente casi un 50% de los casos permanezca sin diagnosticar. Aproximadamente, un 6-10% de los casos de retraso mental inespecífico se debe a microdeleciones o microduplicaciones en regiones subteloméricas de los cromosomas. Algunos de estos síndromes confieren un fenotipo clínicamente reconocible, como es el caso del síndrome 1p36 o la microdeleción 22q13.33, pero otros afectan a pocos pacientes y son todavía poco reconocidos. Pacientes y métodos. Se ha analizado a 300 pacientes afectados de retraso mental para reordenamientos de las regiones subteloméricas mediante una técnica sencilla, rápida y poco costosa como es la amplificación múltiple dependiente de ligación (MLPA). Resultados. Un 5,3% de los pacientes presentaron reordenamientos subteloméricos; el 75% de los casos corresponde a casos de novo, el 18,7% fueron heredados de alguno de los dos progenitores. En 14 casos las alteraciones detectadas pudieron considerarse como causantes del fenotipo que presentaban los pacientes, y en dos casos, como posibles polimorfismos. Conclusiones. Se confirma la elevada frecuencia de reordenamientos subteloméricos como causa de retraso mental y se refuerza la idea de analizar de forma rutinaria las regiones subteloméricas para llegar a un diagnóstico, establecer una correlación genotipo-fenotipo detallada y poder ofrecer un consejo genético adecuado (AU)

Introduction. The study of mental retardation is one of the most complex fields in human genetics due to its high degree of clinical and genetic heterogeneity. About 50% of cases of mental retardation remain undiagnosed. It is known that about 6-10% of cases are due to subtelomeric rearrangements. Some of these are responsible for a clinically recognized phenotype, i.e. 1p36 or 22q13.33 microdeletion syndromes, but others affect few patients and are not well characterized. Patients and methods. We have analyzed 300 consecutive mentally retarded patients for subtelomeric rearrangements by MLPA. Results. About 5.3% of patients presented subtelomeric rearrangements; from these, 75% contained de novo rearrangements and 18.7% included inherited aberrations from a healthy parent. In 14 cases, aberrations were likely related to disease and in two cases were putative polymorphisms. Conclusions. This study confirms the high frequency of subtelomeric rearrangements in mental retardation and reinforces the idea of a routine subtelomeric screening in these patients in order to get a correct diagnosis, establish genotypephenotype correlations and offer an accurate genetic counseling (AU)

Fragile X syndrome prenatal diagnosis: parental attitudes and reproductive responses.

Fragile X syndrome (FXS) is the most common inherited form of mental retardation. It is caused by a CGG repeat expansion, which results in hypermethylation and silencing of the FMR1 gene. The results from 213 FXS prenatal diagnoses performed in the study centre were reviewed. Family history of FXS or undiagnosed mental retardation (MR) were the reasons for referral and 64% of mothers were not aware of their status so prenatal and mother tests were performed at the same time. Among those women referred for family history of unknown MR, 17.6% were found to be FXS carriers. The attitudes and perceptions of the syndrome of 52 FXS carriers were also evaluated. Most of them had been diagnosed as carriers when the child was already born and the most common feeling was sadness, followed by impotence and guilt. The majority of them had received genetic counselling and they considered it useful. Regarding reproductive options, prenatal diagnosis was chosen by 40.5% of women. Prenatal diagnosis for FXS is a good reproductive option and it should be carried out whenever family history of MR is present. A high percentage of FXS carriers are detected following this approach.

Deletion of the OPHN1 gene detected by aCGH.

BACKGROUND: The oligophrenin 1 gene (OPHN1) is an Rho-GTPase-activating protein involved in the regulation of the G-protein cycle required for dendritic spine morphogenesis. Mutations in this gene are implicated in X-linked mental retardation (XLMR). METHODS: We report a deletion spanning exons 21 and 22 of the OPHN1 gene identified by a tiling path X-chromosome array comparative genomic hybridization (CGH) and multiplex ligation-dependent probe amplification, confirmed by polymerase chain reaction (PCR), in a family with four males with intellectual disabilities. RESULTS: Patients harbouring mutations in this gene share the same clinical manifestations reinforcing the idea of a syndromic XLMR. The most important neurological findings are cerebellar hypoplasia and ventriculomegaly. CONCLUSIONS: We recommend screening of the OPHN1 gene in male patients with XLMR and cerebellar anomalies. This case highlights the value of high-resolution techniques as Multiplex Ligation Probe Amplification (MLPA) and CGH array for a better characterization of copy number changes and suggests that MLPA technology may be very useful for an initial screening of small deletions and duplications in XLMR patients.

X-chromosome tiling path array detection of copy number variants in patients with chromosome X-linked mental retardation.

BACKGROUND: Aproximately 5-10% of cases of mental retardation in males are due to copy number variations (CNV) on the X chromosome. Novel technologies, such as array comparative genomic hybridization (aCGH), may help to uncover cryptic rearrangements in X-linked mental retardation (XLMR) patients. We have constructed an X-chromosome tiling path array using bacterial artificial chromosomes (BACs) and validated it using samples with cytogenetically defined copy number changes. We have studied 54 patients with idiopathic mental retardation and 20 controls subjects. RESULTS: Known genomic aberrations were reliably detected on the array and eight novel submicroscopic imbalances, likely causative for the mental retardation (MR) phenotype, were detected. Putatively pathogenic rearrangements included three deletions and five duplications (ranging between 82 kb to one Mb), all but two affecting genes previously known to be responsible for XLMR. Additionally, we describe different CNV regions with significant different frequencies in XLMR and control subjects (44% vs. 20%). CONCLUSION: This tiling path array of the human X chromosome has proven successful for the detection and characterization of known rearrangements and novel CNVs in XLMR patients.

Contiguous deletion of the NDP, MAOA, MAOB, and EFHC2 genes in a patient with Norrie disease, severe psychomotor retardation and myoclonic epilepsy.

Norrie disease (ND) is an X-linked disorder, inherited as a recessive trait that, therefore, mostly affects males. The gene responsible for ND, called NDP, maps to the short arm of chromosome X (Xp11.4-p11.3). We report here an atypical case of ND, consisting of a patient harboring a large submicroscopic deletion affecting not only the NDP gene but also the MAOA, MAOB, and EFHC2 genes. Microarray comparative genomic hybridization (CGH) analysis showed that 11 consecutive bacterial artificial chromosome (BAC) clones, mapping around the NDP gene, were deleted. These clones span a region of about 1 Mb on Xp11.3. The deletion was ascertained by fluorescent in situ hybridization (FISH) analysis with different BAC clones located within the region. Clinical features of the proband include bilateral retinal detachment, microcephaly, severe psychomotor retardation without verbal language skills acquired, and epilepsy. The identification and molecular characterization of this case reinforces the idea of a new contiguous gene syndrome that would explain the complex phenotype shared by atypical ND patients.

Screening for MECP2 mutations in Spanish patients with an unexplained mental retardation.

Rett syndrome (RTT) is an X-linked progressive encephalopathy. Mutations in the MECP2 (methyl-CpG-binding protein) gene have been found to cause RTT. In the past few years, the role of MECP2 mutations in patients with mental disorders other than RTT has been studied, finding that mutations in MECP2 also contribute to non-syndromic entities. More recently, it has been demonstrated that RTT shares clinical features with those of Angelman syndrome, another neurodevelopmental disorder. These observations must be confirmed in a large series, to better understand the criteria needed for justifying a molecular test. Consequently, we have searched for MECP2 mutations in 294 patients (43 Angelman and Prader-Willi like included) with mental retardation (MR) of unknown aetiology. We found six polymorphisms (three novel, three previously reported) in 10 patients, one novel unclassified silent change (p.V222V) in a man, and one causative mutation in a girl with MR. Once this case was clinically reviewed, the girl presented symptoms of atypical RTT. The mutation (p.Y141C) lies within the methyl-binding domain, and has only been reported once in another atypical RTT. Our results show that the MECP2 mutations account for a low frequency (1/416 chromosomes = 0.24%) among mentally retarded individuals, which imply that it is necessary to perform an exhaustive clinical examination of patients before determining whether analysis of MECP2 is required or not.

Elastin mutation screening in a group of patients affected by vascular abnormalities.

Supravalvular aortic stenosis is an uncommon but well-characterized congenital form of left ventricular outflow obstruction. The lesion involves the ascending aorta and often occurs in association with pulmonary arterial stenoses or stenoses of other arteries, especially at major branch points. It can occur sporadically, as an autosomal dominant condition, or as one component of Williams-Beuren syndrome. In fact, the clinical and structural characteristics of supravalvular aortic stenosis are identical in both syndromic and nonsyndromic cases. The severity of supravalvular aortic stenosis varies; but if it is left untreated, it may result in heart failure, myocardial infarction, and sudden death. Supravalvular aortic stenosis in Williams-Beuren patients occurs as a consequence of a complete deletion of one copy of the elastin gene on chromosome 7q11.23. However, the underlying genetic cause of isolated supravalvular aortic stenosis has been identified as translations, gross intragenic deletions, and point mutations that disrupt the elastin gene. We report the results obtained in a mutation screening of the elastin gene in 28 patients with supravalvular aortic stenosis and other vascular abnormalities. The aim of the screening was to characterize the molecular cause of this lesion. We have detected 11 changes, including nine polymorphisms and two novel putative missense mutations.

Analysis of CGG variation through 642 meioses in Fragile X families.

Fragile X syndrome is the commonest familial form of inherited mental retardation. The molecular defect is an expansion of the CGG trinucleotide repeats in the 5' untranslated region of the FMR1 gene that is inherited in an unstable fashion in fragile X families. In an attempt to provide more information about the CGG tract intergenerational variation, we have evaluated 642 transmissions in 175 Fragile X families. PCR and Southern blot (StB12.3) was used to analyse the CGG number. Among premutated alleles, 90.2% showed expansion, two-thirds to a full mutation while the rest remained in the premutation range, 5.5% of alleles did not vary and finally 4.3% of them reduced in size. Premutated females showed an increased risk of expansion to the full mutation depending on the CGG tract. The estimated risk for 80 triplets is more than seven times that of a woman carrying 59 CGG, the risk being 100% for alleles of >100 repeats. Fifty-nine repeats was the smallest allele that expanded to full mutation. Contractions were detected more frequently in males than in females, being statistically significant. This study contributes to the literature by increasing the data available regarding transmissions in Fragile X families and it allows us to perform more precise genetic counselling for women with the CGG repeat in the premutation range.

Cryptic chromosomal rearrangement screening in 30 patients with mental retardation and dysmorphic features.

Mental retardation affects 1-3% of the general population, and the genetic causes in many cases are unknown. Cytogenetically undetected chromosomal imbalances have been indicated as an explanation. Nowadays, due to the development of molecular cytogenetic techniques, it is possible to identify cryptic rearrangements involving the ends of chromosomes. We report a screening using chromosome-specific telomere fluorescence in-situ hybridization (FISH) probes, in a group of 30 patients with a well-characterized phenotype including mental retardation, dysmorphic features, and a normal karyotype. Among them, two subtelomeric rearrangements have been detected and characterized. One of them is a de novo deletion of 1p36, which has been previously described as a new contiguous gene syndrome. The second is an unbalanced product of a cryptic translocation involving chromosomes 1 and 13, which results in a partial 1q trisomy and partial 13q monosomy. These findings highlight, the importance of searching for cryptic subtelomeric rearrangements in non-syndromic mentally retarded patients.