Mortality in Patients with 22q11.2 Rearrangements.

The 22q11.2 region is highly susceptible to genomic rearrangements leading to multiple genomic disorders, including 22q11.2 microdeletion syndrome (22q11.2 DS) (MIM# 188400), 22q11.2 microduplication syndrome (MIM# 608363), supernumerary der(22)t(11;22) syndrome (also known as Emanuel Syndrome; MIM# 609029), and Cat Eye Syndrome (MIM# 115470). In this study, we present data on causes of mortality, average age of death, and the existing associated risk factors in patients with 22q11.2 rearrangements. Our cohort included 223 patients (120 males and 103 females) with confirmed diagnoses of 22q11.2 rearrangements diagnosed through molecular techniques (FISH, MLPA, and CMA). Relatives from patients who have been molecularly confirmed with 22q11.2 rearrangements have also been added to the study, regardless of the presence or absence of symptoms. Of these 223 individuals, 21 (9.4%) died. Deceased patients' rearrangements include 19 microdeletions, 1 microduplication, and 1 patient with a marker chromosome. The median age of death was 3 months and 18 days (ranging from 3 days to 34 years). There were 17 patients who died at pediatric age (80.95%), 3 died at adult age (14.28%), and for 1 of whom, the age of death is unknown (4.76%). Eighteen patients were White Mediterranean (European non-Finnish) (85.71%) whereas three were Amerindian (South American) (14.28%). Mortality from cardiac causes accounted for 71.42%. The second most frequent cause of death was sepsis in two patients (9.52%). One patient died from respiratory failure (4.76%) and one from renal failure (4.76%). Information regarding the cause of death was not available in two patients (9.52%). Most patients who died were diagnosed within the first week of life, the majority on the first day. This study adds additional information on mortality in one of the largest cohorts of patients with 22q11.2 rearrangements in more than 30 years of follow-up.

Is Nuchal Translucency of 3.0-3.4 mm an Indication for cfDNA Testing or Microarray? - A Multicenter Retrospective Clinical Cohort Study.

INTRODUCTION: This study aimed to evaluate the occurrence of clinically relevant (sub)microscopic chromosomal aberrations in fetuses with the nuchal translucency (NT) range from 3.0 to 3.4 mm, which would be potentially missed by cfDNA testing. METHODS: A retrospective data analysis of 271 fetuses with NT between 3.0 and 3.4 mm and increased first trimester combined test (CT) risk in five cohorts of pregnant women referred for invasive testing and chromosomal microarray was performed. RESULTS: A chromosomal aberration was identified in 18.8% fetuses (1:5; 51/271). In 15% (41/271) of cases, trisomy 21, 18, or 13 were found. In 0.7% (2/271) of cases, sex chromosome aneuploidy was found. In 1.1% (3/271) of cases, CNV >10 Mb was detected, which would potentially also be detected by genome-wide cfDNA testing. The residual risk for missing a submicroscopic chromosome aberration in the presented cohorts is 1.8% (1:54; 5/271). CONCLUSION: Our results indicate that a significant number of fetuses with increased CT risk and presenting NT of 3.0-3.4 mm carry a clinically relevant chromosomal abnormality other than common trisomy. Invasive testing should be offered, and counseling on NIPT should include the test limitations that may result in NIPT false-negative results in a substantial percentage of fetuses.

Chromosomal Microarray in Patients with Non-Syndromic Autism Spectrum Disorders in the Clinical Routine of a Tertiary Hospital.

Autism spectrum disorders (ASD) comprise a group of neurodevelopmental disorders (NDD) characterized by deficits in communication and social interaction, as well as repetitive and restrictive behaviors, etc. The genetic implications of ASD have been widely documented, and numerous genes have been associated with it. The use of chromosomal microarray analysis (CMA) has proven to be a rapid and effective method for detecting both small and large deletions and duplications associated with ASD. In this article, we present the implementation of CMA as a first-tier test in our clinical laboratory for patients with primary ASD over a prospective period of four years. The cohort was composed of 212 individuals over 3 years of age, who met DSM-5 diagnostic criteria for ASD. The use of a customized array-CGH (comparative genomic hybridization) design (KaryoArray®) found 99 individuals (45.20%) with copy number variants (CNVs); 34 of them carried deletions (34.34%) and 65 duplications (65.65%). A total of 28 of 212 patients had pathogenic or likely pathogenic CNVs, representing approximately 13% of the cohort. In turn, 28 out of 212 (approximately 12%) had variants of uncertain clinical significance (VUS). Our findings involve clinically significant CNVs, known to cause ASD (syndromic and non-syndromic), and other CNVs previously related to other comorbidities such as epilepsy or intellectual disability (ID). Lastly, we observed new rearrangements that will enhance the information available and the collection of genes associated with this disorder. Our data also highlight that CMA could be very useful in diagnosing patients with essential/primary autism, and demonstrate the existence of substantial genetic and clinical heterogeneity in non-syndromic ASD individuals, underscoring the continued challenge for genetic laboratories in terms of its molecular diagnosis.

Variability in Phelan-McDermid Syndrome in a Cohort of 210 Individuals.

Phelan-McDermid syndrome (PMS, OMIM# 606232) results from either different rearrangements at the distal region of the long arm of chromosome 22 (22q13.3) or pathogenic sequence variants in the SHANK3 gene. SHANK3 codes for a structural protein that plays a central role in the formation of the postsynaptic terminals and the maintenance of synaptic structures. Clinically, patients with PMS often present with global developmental delay, absent or severely delayed speech, neonatal hypotonia, minor dysmorphic features, and autism spectrum disorders (ASD), among other findings. Here, we describe a cohort of 210 patients with genetically confirmed PMS. We observed multiple variant types, including a significant number of small deletions (<0.5 Mb, 64/189) and SHANK3 sequence variants (21 cases). We also detected multiple types of rearrangements among microdeletion cases, including a significant number with post-zygotic mosaicism (9.0%, 17/189), ring chromosome 22 (10.6%, 20/189), unbalanced translocations (de novo or inherited, 6.4%), and additional rearrangements at 22q13 (6.3%, 12/189) as well as other copy number variations in other chromosomes, unrelated to 22q deletions (14.8%, 28/189). We compared the clinical and genetic characteristics among patients with different sizes of deletions and with SHANK3 variants. Our findings suggest that SHANK3 plays an important role in this syndrome but is probably not uniquely responsible for all the spectrum features in PMS. We emphasize that only an adequate combination of different molecular and cytogenetic approaches allows an accurate genetic diagnosis in PMS patients. Thus, a diagnostic algorithm is proposed.

Mosaic Variegated Aneuploidy syndrome 2 caused by biallelic variants in CEP57, two new cases and review of the phenotype.

Mosaic Variegated Aneuploidy Syndrome 2 (MVA2; MIM 614114) is a rare autosomal recessive disorder, characterized by mosaic aneuploidies involving multiple chromosomes and tissues, caused by biallelic pathogenic variants in the CEP57 gene. Only 10 patients have been reported to date. We report two additional non related cases born to Moroccan consanguineous parents, carrying the previously described c.915_925dup11 CEP57 homozygous variant. Common features of these 12 cases include growth retardation, typically of prenatal onset, distinctive facial features, endocrine, cardiovascular and skeletal, abnormalities while malignancies have not been reported. This report describes the phenotypical spectrum of MVA2.

Deep Phenotyping and Genetic Characterization of a Cohort of 70 Individuals With 5p Minus Syndrome.

Chromosome-5p minus syndrome (5p-Sd, OMIM #123450) formerly known as Cri du Chat syndrome results from the loss of genetic material at the distal region of the short arm of chromosome 5. It is a neurodevelopmental disorder of genetic cause. So far, about 400 patients have been reported worldwide. Individuals affected by this syndrome have large phenotypic heterogeneity. However, a specific phenotype has emerged including global developmental delay, microcephaly, delayed speech, some dysmorphic features, and a characteristic and monochromatic high-pitch voice, resembling a cat's cry. We here describe a cohort of 70 patients with clinical features of 5p- Sd characterized by means of deep phenotyping, SNP arrays, and other genetic approaches. Individuals have a great clinical and molecular heterogeneity, which can be partially explained by the existence of additional significant genomic rearrangements in around 39% of cases. Thus, our data showed significant statistical differences between subpopulations (simple 5p deletions versus 5p deletions plus additional rearrangements) of the cohort. We also determined significant "functional" differences between male and female individuals.

Prenatal ultrasound findings in Koolen-de Vries foetuses: Central nervous system anomalies are frequent markers of this syndrome.

OBJECTIVE: Prenatal diagnoses of microdeletion syndromes without ultrasound findings in the first and second trimester are always difficult. The objective of this study is to report the prenatal ultrasound findings in four foetuses diagnosed with 17q21.31 microdeletions (Koolen-de Vries syndrome) using chromosomal microarrays (CMA). PATIENTS AND METHODS: We present four foetuses with 17q21.31 microdeletion. All showed CNS anomalies in the third trimester, three had ventriculomegaly, and one hypogenesis of corpus callosum at 31 weeks of pregnancy. RESULTS: Array-SNPs and CGH-array were performed on uncultured amniocytes and peripheral blood revealing a 17q21.31 microdeletion. CONCLUSIONS: Prenatal CNS anomalies (mainly ventriculomegaly) at third trimester, in spite of isolate, should be considered a prenatal ultrasound marker of this syndrome. This kind of malformations raise the possibility of an underlying genetic conditions including 17q21.31 microdeletion; thus, CMA should be taken into consideration when offering prenatal genetic counselling.

Prenatal diagnosis of fetal skeletal dysplasias in a tertiary Hospital in Spain.

OBJECTIVE: To assess the diagnostic accuracy of prenatal ultrasound for detecting fetal skeletal dysplasias and to describe its role in orienting genetic studies. STUDY DESIGN: Observational study of pregnant women surveyed in our hospital, between 2011 and 2018, with fetal long bones below the 3rd centile (shortened long bones), either as an isolated finding or associated to other skeletal anomalies. We used a systematic protocol for the ultrasound evaluation and selection of those fetuses suspected of having a skeletal dysplasia. We report the demographics of these patients along with the sonographic follow-up of their fetuses, the genetic results and the outcome of the pregnancies and the newborn in the entire group and also compare data between the two sub-groups (isolated shortened long bones vs shortened long bones associated to other anomalies). RESULTS: A total of 81 pregnancies with a suspected fetal skeletal dysplasia were included, with a complete follow-up available in 75 cases, 22 with isolated shortened long bones and 53 cases that presented shortened long bones with other skeletal anomalies. In the shortened long bones sub-group, a total of five (23 %) were born healthy neonates, 10 (45 %) were small for gestational age or intrauterine growth restricted (one of them of genetic origin) and seven (32 %) had a skeletal dysplasia (6 of them with genetic diagnosis). Whilst among the 53 cases that presented with shortened long bones + other skeletal anomalies, three (6%) were healthy neonates, five (9%) were small for gestational age/intrauterine growth restricted (two of genetic origin) and 45 (85 %) had a skeletal dysplasia (19 genetically confirmed and 26 with a clinical diagnosis). These differences in frequencies between the two sub-groups were determined to be statistically significant (χ2: p = 0.02). CONCLUSION: Around one third of fetuses with isolated shortened long bones will have a skeletal dysplasia. If abnormal skeletal ultrasound findings are associated with shortened long bones, the risk for skeletal dysplasia is significantly increased (85 %). Prenatal systematic approach in a multidisciplinary unit is useful in the orientation of genetic studies.

Gestación gemelar con mola hidatidiforme completa y feto vivo coexistente tras una fecundación in vitro / Twin gestation with complete hydatidiform mole and coexisting live fetus after in vitro fertilization

Se presenta el caso de una paciente de 39 años con embarazo gemelar bicorial biamniótico en el que coexistían una gestación evolutiva y una mola hidatidiforme completa. La gestación había sido conseguida mediante técnicas de reproducción asistida. Tras el diagnóstico ecográfico, se confirmó el diagnóstico de mola hidatiforme mediante biopsia corial. Se realizó un manejo conservador de la gestación hasta que se desencadenó un parto prematuro en la semana 24+5 de gestación. El recién nacido falleció por complicaciones asociadas a la prematuridad. La mujer completó el seguimiento en nuestro centro de forma satisfactoria

We present the case of a 39 year-old patient with a bicorial biamniotic twin pregnancy in which an evolutio-nary gestation and a complete hydatidiform mole coexisted. The gestation had been achieved through assisted reproduction techniques. After the ultrasound diagnosis, the diagnosis of hydatidiform mole was confirmed by chorionic biopsy. A conservative management of pregnancy was performed until a premature birth was triggered in the 24 + 5 week of gestation. The newborn died due to complications associated with prematurity

Deterioro funcional asociado a la hospitalización en pacientes mayores de 65 años / Hospitalisation as a risk for functional decline in older adults

El deterioro funcional es un riesgo asociado a la hospitalización en las personas mayores, con elevada prevalencia (35-70%) y graves consecuencias. OBJETIVO: Determinar la incidencia del deterioro funcional relacionado con la hospitalización (DFH) en personas mayores ingresadas en el Área Médica del Complejo Hospitalario Universitario de Albacete. MÉTODO: Se ha realizado un estudio de cohortes, cuya variable principal ha sido el DFH (pérdida de capacidad para realizar actividades cotidianas durante el ingreso y tras el alta); se han incluido otras variables (demográficas, relacionadas con el ingreso, patologías asociadas, estado cognitivo). Los datos se recogieron por entrevista presencial al paciente y cuidadores, llamada telefónica tras el alta y revisión de historia clínica. RESULTADOS: Se incluyeron 104 pacientes, de los que un 51,9% eran mujeres; la edad media fue 79,97 años (dt = 7,89), IC 95% [78,43; 81,5] y la estancia media de 10,11 días (dt = 7,65) IC 95% [8,62; 11,6]. El primer día del ingreso 43 (41,4%) pacientes presentaban estado mental intacto. Se produjo DFH en las primeras 24 horas en 60 (57,7%) pacientes; tras el alta hospitalaria, el deterioro existía en un 32,6% de los 92 pacientes que pudieron ser evaluados. En pacientes que antes del ingreso eran independientes para las actividades cotidianas, un 19% quedó con dependencia importante. El DFH se relacionó de forma estadísticamente significativa con los antecedentes de caídas y la edad. CONCLUSIONES: El DFH se produce en un porcentaje elevado de los mayores de 65 años; entre los previamente independientes, casi la quinta parte queda en situación de dependencia

Functional decline: (FD) is a risk associated with hospital admission in older people, due to its high prevalence (35-70%) and its serious consequences. AIM: To determine the incidence of FD in the elderly after hospital admission at the Geriatric and Internal Medicine wards of a tertiary teaching hospital (Albacete, Spain). METHOD: A cohort study has been designed, whose primary focus was FD, defined as the loss of independence to perform the activities of daily living between preadmission status and discharge. Demographic characteristics, comorbidity, length of hospital stay and cognitive status have been analysed. Data collection was performed by interviews with patients and caregivers during hospitalization and after discharge (by phone), as well as by revision of clinical records. RESULTS: 104 patients were evaluated, of which 51.9% were female; the average age was 79.97 years (dt = 7.89) IC 95% [78.43, 81.5] and the average length of stay was 10.11 days (dt = 7.65) IC 95% [8.62,11.6]. The proportion of patients who showed a normal cognitive status on the first in-hospital day was 41.4% (43 patients). FD was present in 60 (57.7%) patients in the first day of hospitalisation; when discharged, 32.6% of 92 patients who could be evaluated showed FD.19% of patients who were previously independent in activities of daily living developed a serious dependence after discharge. FD was associated statistically with age and a history of previous falls. CONCLUSIONS: FD takes place in a high percentage of the elderly PATIENTS: Among the previously independent patients, 19% remains in a situation of dependence after discharge

[Hospitalisation as a risk for functional decline in older adults]. / Deterioro funcional asociado a la hospitalización en pacientes mayores de 65 años.

UNLABELLED: FUNCTIONAL DECLINE: (FD) is a risk associated with hospital admission in older people, due to its high prevalence (35-70%) and its serious consequences. AIM: To determine the incidence of FD in the elderly after hospital admission at the Geriatric and Internal Medicine wards of a tertiary teaching hospital (Albacete, Spain). METHOD: A cohort study has been designed, whose primary focus was FD, defined as the loss of independence to perform the activities of daily living between preadmission status and discharge. Demographic characteristics, comorbidity, length of hospital stay and cognitive status have been analysed. Data collection was performed by interviews with patients and caregivers during hospitalization and after discharge (by phone), as well as by revision of clinical records. RESULTS: 104 patients were evaluated, of which 51.9% were female; the average age was 79.97 years (dt=7.89) IC 95% [78.43, 81.5] and the average length of stay was 10.11 days (dt=7.65) IC 95% [8.62,11.6]. The proportion of patients who showed a normal cognitive status on the first in-hospital day was 41.4% (43 patients). FD was present in 60 (57.7%) patients in the first day of hospitalisation; when discharged, 32.6% of 92 patients who could be evaluated showed FD. 19% of patients who were previously independent in activities of daily living developed a serious dependence after discharge. FD was associated statistically with age and a history of previous falls. CONCLUSIONS: FD takes place in a high percentage of the elderly patients. Among the previously independent patients, 19% remains in a situation of dependence after discharge.

Analysis of invdupdel(8p) rearrangement: Clinical, cytogenetic and molecular characterization.

Inverted duplication 8p associated with deletion of the short arms of chromosome 8 (invdupdel[8p]) is a relatively uncommon complex chromosomal rearrangement, with an estimated incidence of 1 in 10,000-30,000 live borns. The chromosomal rearrangement consists of a deletion of the telomeric region (8p23-pter) and an inverted duplication of the 8p11.2-p22 region. Clinical manifestations of this disorder include severe to moderate intellectual disability and characteristic facial features. In most cases, there are also CNS associated malformations and congenital heart defects. In this work, we present the cytogenetic and molecular characterization of seven children with invdupdel(8p) rearrangements. Subsequently, we have carried out genotype-phenotype correlations in these seven patients. The majority of our patients carry a similar deletion but different size of duplications; the latter probably explaining the phenotypic variability among them. We recommend that complete clinical evaluation and detailed chromosomal microarray studies should be undertaken, enabling appropriate genetic counseling.

Familial imbalance in 16p13.11 leads to a dosage compensation rearrangement in an unaffected carrier.

BACKGROUND: We and others have previously reported that familial cytogenetic studies in apparently de novo genomic imbalances may reveal complex or uncommon inheritance mechanisms. METHODS: A familial, combined genomic and cytogenetic approach was systematically applied to the parents of all patients with unbalanced genome copy number changes. RESULTS: Discordant array-CGH and FISH results in the mother of a child with a prenatally detected 16p13.11 interstitial microduplication disclosed a balanced uncommon rearrangement in this chromosomal region. Further dosage and haplotype familial studies revealed that both the maternal grandfather and uncle had also the same 16p duplication as the proband. Genomic compensation observed in the mother probably occurred as a consequence of interchromosomal postzygotic nonallelic homologous recombination. CONCLUSIONS: We emphasize that such a dualistic strategy is essential for the full characterization of genomic rearrangements as well as for appropriate genetic counseling.

A new overgrowth syndrome is due to mutations in RNF125.

Overgrowth syndromes (OGS) are a group of disorders in which all parameters of growth and physical development are above the mean for age and sex. We evaluated a series of 270 families from the Spanish Overgrowth Syndrome Registry with no known OGS. We identified one de novo deletion and three missense mutations in RNF125 in six patients from four families with overgrowth, macrocephaly, intellectual disability, mild hydrocephaly, hypoglycemia, and inflammatory diseases resembling Sjögren syndrome. RNF125 encodes an E3 ubiquitin ligase and is a novel gene of OGS. Our studies of the RNF125 pathway point to upregulation of RIG-I-IPS1-MDA5 and/or disruption of the PI3K-AKT and interferon signaling pathways as the putative final effectors.

New microdeletion and microduplication syndromes: A comprehensive review.

Several new microdeletion and microduplication syndromes are emerging as disorders that have been proven to cause multisystem pathologies frequently associated with intellectual disability (ID), multiple congenital anomalies (MCA), autistic spectrum disorders (ASD) and other phenotypic findings. In this paper, we review the "new" and emergent microdeletion and microduplication syndromes that have been described and recognized in recent years with the aim of summarizing their main characteristics and chromosomal regions involved. We decided to group them by genomic region and within these groupings have classified them into those that include ID, MCA, ASD or other findings. This review does not intend to be exhaustive but is rather a quick guide to help pediatricians, clinical geneticists, cytogeneticists and/or molecular geneticists.

Customized high resolution CGH-array for clinical diagnosis reveals additional genomic imbalances in previous well-defined pathological samples.

High-resolution array comparative genomic hybridization (aCGH) is a powerful molecular cytogenetic tool that is being adopted for diagnostic evaluation of genomic imbalances and study disease mechanisms and pathogenesis. We report on the design and use, of a custom whole-genome oligonucleotide-based array (called KaryoArray®v3.0; Agilent-based 8 × 60 K) for diagnostic setting, which was able to detect new and unexpected rearrangements in 11/63 (~17.5%) of previous known pathological cases associated with known genetic disorders, and in the second step it identified at least one causal genomic imbalance responsible of the phenotype in ~20% of patients with psychomotor development delay and/or intellectual disability. To validate the array, first; we blindly tested 120 samples; 63 genomic imbalances that had previously been detected by karyotyping, FISH and/or MLPA, and 57 sex-matched control samples from healthy individuals; secondly a prospective study of 540 patients with intellectual disabilities, autism spectrum disorder and multiple congenital anomalies were evaluated to confirm the utility of the tool. These data indicate that implementation of array technologies as the first-tier test may reveal that additional genomic imbalances could co-exist in patients with trisomies and classical del/dup syndromes, suggesting that aCGH may also be indicated in these individuals, at least when phenotype does not match completely with genotype.

Diagnóstico prenatal y array-hibridación genómica comparada (CGH) (I). Gestaciones de elevado riesgo / Prenatal diagnosis and comparative genomic hybridization (CGH) -array (I). High risk pregnancies

Objetivos. Revisar los principios de los microarrays (en concreto array-CGH [a-CGH]), sus beneficios para el diagnóstico prenatal y los desafíos asociados, a través de los trabajos actualmente publicados y aquellos derivados de nuestra experiencia práctica en los dos últimos años. Métodos. Revisión de la literatura y comparación con estudios prospectivos y retrospectivos con array-CGH en casos de gestaciones con elevado riesgo (preferentemente con alteraciones ecográficas). Resultados. La tasa de detección de alteraciones genómicas por a-CGH en nuestros casos con alteraciones ecográficas fue de entre el 13,3 y el 15%. Conclusión. La combinación de la mayor capacidad de los microarrays en el cribado del genoma humano para la detección de cambios en números de copias, dentro de un único ensayo experimental, así como su mayor resolución técnica en casos de gestaciones de elevado riesgo, podría convertir a los array-CGH, en la próxima década, en una alternativa muy interesante para reemplazar al cariotipo convencional como test diagnóstico de primera línea, en estos casos(AU)

Objectives. Review the principles of microarrays (in particular array-CGH), their benefits for prenatal diagnosis and the associated challenges, through the currently published works and those derived from our practical experience over the past two years. Methods. A literature review was carried out, as well as comparisons with prospective and retrospective studies with array-CGH in cases of pregnancies at high risk (preferably with ultrasound anomalies). Results. The detection rate of genomic alterations by array-CGH in our cases with ultrasound anomalies was between 13.3-15%. Conclusion. The combination of the increased capacity of microarrays in screening of the human genome to detect changes in copy numbers variations, within a single experimental assay, as well as their greater technical resolution in cases of high-risk pregnancies, could lead to array-CGH to be a very interesting diagnostic approach in the next decade to replace the karyotype as a gold standard in such prenatal studies(AU)

Clinical utility of chromosomal microarray analysis in invasive prenatal diagnosis.

Novel methodologies for detection of chromosomal abnormalities have been made available in the recent years but their clinical utility in prenatal settings is still unknown. We have conducted a comparative study of currently available methodologies for detection of chromosomal abnormalities after invasive prenatal sampling.A multicentric collection of a 1-year series of fetal samples with indication for prenatal invasive sampling was simultaneously evaluated using three screening methodologies: (1) karyotype and quantitative fluorescent polymerase chain reaction (QF-PCR), (2) two panels of multiplex ligation-dependent probe amplification (MLPA), and (3) chromosomal microarray-based analysis (CMA) with a targeted BAC microarray. A total of 900 pregnant women provided informed consent to participate (94% acceptance rate). Technical performance was excellent for karyotype, QF-PCR, and CMA (~1% failure rate), but relatively poor for MLPA (10% failure). Mean turn-around time (TAT) was 7 days for CMA or MLPA, 25 for karyotype, and two for QF-PCR, with similar combined costs for the different approaches. A total of 57 clinically significant chromosomal aberrations were found (6.3%), with CMA yielding the highest detection rate (32% above other methods). The identification of variants of uncertain clinical significance by CMA (17, 1.9%) tripled that of karyotype and MLPA, but most alterations could be classified as likely benign after proving they all were inherited. High acceptability, significantly higher detection rate and lower TAT, could justify the higher cost of CMA and favor targeted CMA as the best method for detection of chromosomal abnormalities in at-risk pregnancies after invasive prenatal sampling.

Characterization of a 8q21.11 microdeletion syndrome associated with intellectual disability and a recognizable phenotype.

We report eight unrelated individuals with intellectual disability and overlapping submicroscopic deletions of 8q21.11 (0.66-13.55 Mb in size). The deletion was familial in one and simplex in seven individuals. The phenotype was remarkably similar and consisted of a round face with full cheeks, a high forehead, ptosis, cornea opacities, an underdeveloped alae, a short philtrum, a cupid's bow of the upper lip, down-turned corners of the mouth, micrognathia, low-set and prominent ears, and mild finger and toe anomalies (camptodactyly, syndactyly, and broadening of the first rays). Intellectual disability, hypotonia, decreased balance, sensorineural hearing loss, and unusual behavior were frequently observed. A high-resolution oligonucleotide array showed different proximal and distal breakpoints in all of the individuals. Sequencing studies in three of the individuals revealed that proximal and distal breakpoints were located in unique sequences with no apparent homology. The smallest region of overlap was a 539.7 kb interval encompassing three genes: a Zinc Finger Homeobox 4 (ZFHX4), one microRNA of unknown function, and one nonfunctional pseudogen. ZFHX4 encodes a transcription factor expressed in the adult human brain, skeletal muscle, and liver. It has been suggested as a candidate gene for congenital bilateral isolated ptosis. Our results suggest that the 8q21.11 submicroscopic deletion represents a clinically recognizable entity and that a haploinsufficient gene or genes within the minimal deletion region could underlie this syndrome.