Cat eye syndrome: Clinical, cytogenetics and familial findings in a large cohort of 43 patients highlighting the importance of congenital heart disease and inherited cases.

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.

Supernumerary chromosome 6 marker associated with paternal uniparental isodisomy of chromosome 6 in a patient with a syndromic disorder of insulin secretion.

The association of both uniparental disomy and small supernumerary marker chromosomes is rare. Clinical impact depends on the presence of imprinted genes and/or the unmasking of a recessive mutation of the chromosome involved in the uniparental disomy and the euchromatic content of the sSMC. Here, we report on the second case of a patient harbouring a de novo supernumerary marker chromosome 6 causing partial trisomy 6p12.3p11.1 associated with a paternal uniparental isodisomy of chromosome 6. Our patient presented with intrauterine growth retardation, macroglossia, initial developmental delay and transient neonatal diabetes mellitus followed by a congenital hyperinsulinism. Diabetes and intrauterine growth retardation can be linked to the paternal isodisomy of the imprinted locus on chromosome 6q24 whereas developmental delay is probably due to the small supernumerary marker chromosome. However, the clinical impact of partial trisomy 6p is difficult to address due to a limited number of patients. The careful clinical examination and the molecular characterization of additional patients with trisomy 6p are needed to further predict the phenotype for genetic counselling. Finally, uniparental disomy should be considered when a sSMC involving a chromosome containing imprinted regions is detected, especially in the prenatal setting.

Management of copy number variants associated with incomplete penetrance and variable expressivity-Results of a French survey.

Increasing interest regarding neurodevelopmental disorders and democratization of chromosomal microarray analysis have led to growing identification of neuro-susceptibility copy number variations (CNVs). These CNVs have incomplete penetrance and variable expressivity (PIEV), which makes phenotypic features hard to predict. The French Consortium "AchroPuce" has provided a list of 17 CNVs that should be considered as PIEV CNVs. This list led to consensual French practices of healthcare professionals in postnatal diagnosis. However, no consensus was established in prenatal diagnosis and fetal pathology. 121 French health professionals were surveyed their opinions and practices regarding reporting of PIEV CNVs to patients, in order to identify key points so as to establish French recommendations. The survey showed that professionals in favor of reporting PIEV CNVs to patients in prenatal diagnosis and fetal pathology (respectively, 76% and 84% of respondents) considered highlighted that multidisciplinary consultation is the main point-of-care management before family survey. This statement is close to recommendations published worldwide. As a consequence, multidisciplinary expertise should be the basis of French recommendations concerning the reporting of PIEV CNVs and genetic counseling in prenatal diagnosis and fetal pathology.

Copy number variations analysis in a cohort of 47 fetuses and newborns with congenital diaphragmatic hernia.

OBJECTIVES: The congenital diaphragmatic hernia (CDH), characterized by malformation of the diaphragm and lung hypoplasia, is a common and severe birth defect that affects around 1 in 4000 live births. However, the etiology of most cases of CDH remains unclear. The aim of this study was to perform a retrospective analysis of copy number variations (CNVs) using a high-resolution array comparative genomic hybridization (array-CGH) in a cohort of fetuses and newborns with CDH. METHODS: Forty seven fetuses and newborns with either isolated or syndromic CDH were analyzed by oligonucleotide-based array-CGH Agilent 180K technique. RESULTS: A mean of 10.2 CNVs was detected by proband with a total number of 480 CNVs identified based on five categories: benign, likely benign, of uncertain signification, likely pathogenic, and pathogenic. Diagnostic performance was estimated at 19.15% (i.e., likely pathogenic and pathogenic CNVs) for both CDH types. We identified 11 potential candidate genes: COL25A1, DSEL, EYA1, FLNA, MECOM, NRXN1, RARB, SPATA13, TJP2, XIRP2, and ZFPM2. CONCLUSION: We suggest that COL25A1, DSEL, EYA1, FLNA, MECOM, NRXN1, RARB, SPATA13, TJP2, XIRP2, and ZFPM2 genes may be related to CDH occurrence. Thus, this study provides a possibility for new methods of a positive diagnosis.

First prenatal case of Kagami-Ogata syndrome associated with a small supernumerary marker chromosome derived from chromosome 15.

OBJECTIVE: Uniparental disomy (UPD) is one of the common causes of imprinting disorders, which can have an impact on gene expression according to the origin of the parental chromosome. Paternal UPD14 leads to Kagami-Ogata syndrome (KOS), which has a more severe phenotype than maternal UPD14, also called Temple syndrome. Small supernumerary marker chromosomes (SSMCs) are defined as structural chromosomal abnormalities that may be inherited or come from micronucleus-mediated chromothripsis. The association of UPD and SSMC is very rare but not fortuitous and several mechanisms can explain this phenomenon. CASE REPORT: We report the first prenatal case of paternal isodisomy for chromosome 14 associated with a de novo SSMC originating from chromosome 15 and revealed by KOS. The mechanism could be a chromothripsis mediated by trisomy rescue. CONCLUSION: Regarding this case, in relation to a de novo SSMC, it could be important to extend the research of UPD to other acrocentric chromosomes if ultrasound signs are evocative.

Should prenatal chromosomal microarray analysis be offered for isolated fetal growth restriction? A French multicenter study.

BACKGROUND: Compared with standard karyotype, chromosomal microarray analysis improves the detection of genetic anomalies and is thus recommended in many prenatal indications. However, evidence is still lacking on the clinical utility of chromosomal microarray analysis in cases of isolated fetal growth restriction. OBJECTIVE: This study aimed to estimate the proportion of copy number variants detected by chromosomal microarray analysis and the incremental yield of chromosomal microarray analysis compared with karyotype in the detection of genetic abnormalities in fetuses with isolated fetal growth restriction. STUDY DESIGN: This retrospective study included all singleton fetuses diagnosed with fetal growth restriction and no structural ultrasound anomalies and referred to 13 French fetal medicine centers over 1 year in 2016. Fetal growth restriction was defined as an estimated fetal weight of

Early prenatal diagnosis of alveolar capillary dysplasia with misalignment of pulmonary veins due to a 16q24.1 deletion.

First trimester ultrasound screening is an essential fetal examination performed generally at 11-13 weeks of gestation (WG). However, it does not allow for an accurate description of all fetal organs, partly due to their development in progress. Meanwhile, increased nuchal translucency (INT) is a widely used marker known to be associated with chromosomal deleterious rearrangements. We report on a 14 WG fetus with an association of INT and univentricular congenital heart malformation (CHM) leading to chorionic villous sampling (CVS). Cytogenetic investigations performed using array-Comparative Genomic Hybridization (CGH) and fluorescence in situ hybridization (FISH) demonstrated a 1.17 Mb deletion in 16q24.1 encompassing FOXF1 arisen de novo on maternal inherited chromosome. Fetopathological study confirmed CHM with hypoplastic left heart syndrome (HLHS) associating aortic atresia, mitral stenosis, and left ventricular hypoplasia and revealed in addition specific lung lesions corresponding to alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). This is so far the first case of first trimester prenatal diagnosis of ACDMPV due to the deletion of FOXF1 gene. An interpretation of the complex genomic data generated by ultrasound markers is facilitated considerably by the genotype-phenotype correlations on fetopathological examination.

Impact of simulation-based prenatal invasive procedure training on professional practice, a preliminary study.

INTRODUCTION: Amniocentesis and chorionic villus sampling remain the cornerstone of prenatal diagnosis. These procedures are associated with a risk of miscarriage estimated at approximately 0.5 %. Our team has developed a training model for performing simulation-based prenatal invasive procedures. Several simulation sessions are offered each year to obstetricians-gynecologists involved in fetal medicine in France and abroad. This simulation-based learning has already been conclusively evaluated according to levels I and II of the Kirkpatrick model. Here, we carried out a preliminary study according to level III: does participation in training in prenatal invasive procedures through simulation have an influence on professional practice? METHODS: An anonymous online survey was sent to 82 obstetricians-gynecologists who participated in the training in prenatal invasive procedures at the Antoine Béclère maternity hospital between January 1st, 2014 and December 31, 2018. This questionnaire, entitled "Evaluation of the professional impact of training in invasive procedures through simulation", included 20 quantitative and qualitative items. RESULTS: 48 (59 %) obstetricians-gynecologists responded to the questionnaire. 98 % of the participants considered that participation in the training had a significant impact on their professional practice. Half considered this impact to be major. 60 % of the former participants are now attached to a Multidisciplinary Center for Prenatal Diagnosis. CONCLUSION: Participation in training is considered by former participants to have a significant impact on their professional practice. In order to finalize the evaluation of this learning, a study of the benefits for patients and their pregnancy should be discussed.

A case of germline mosaicism for a 7q32.1q33 deletion in a sperm donor: consequences on pregnancy follow-up and recommendations.

BACKGROUND: Germline mosaicism is considered to be a rare event. However, its occurrence is underestimated due to the limited availability of germ cells. The genomic variations that underlie this phenomenon comprise single nucleotide polymorphism (SNPs), copy number variations (CNVs) and aneuploidies. In the case of CNVs, deletions are more frequent in the paternal germline while duplications are more commonly maternal in origin. Germline mosaicism increases with paternal age as the risk of SNPs increase with the number of germ cell divisions. We here report a case of germline mosaicism in the spermatozoa of a donor that resulted in one pathological pregnancy. RESULTS: Straws from the same sperm donor were provided to seven recipient couples, resulting in four pregnancies. Second trimester ultrasound analysis revealed bilateral talipes equinovarus associated with growth retardation in one of these pregnancies. Array-comparative genomic hybridization (CGH) carried out after amniocentesis revealed a 4 Mb deletion in the 7q32.1q33 region. The blood karyotypes and array-CGHs were normal in the mother, as well as in the donor. However, the microsatellite profile indicated a paternal origin. Fluorescent in situ hybridization (FISH) analysis of the donor's spermatozoa revealed the same chromosomal rearrangements in 12% of the spermatozoa population. Due to the documented risk of mental retardation associated with genomic rearrangements in the same region, the couple decided to terminate the pregnancy. Amniocentesis was performed in the other couples, which yielded normal FISH analysis results. CONCLUSIONS: Several cases of germline mosaicism have been reported to date, but their frequency is probably underestimated. Moreover, it is important to note that germline mosaicism cannot be ruled out by conventional cytogenetic screening of blood cells. This case highlights the need for close follow-up of every pregnancy obtained through gamete donation, given that the occurrence of germline mosaicism may have major consequences when multiple pregnancies are obtained concomitantly.

CONTEXTE: La mise en évidence d'une mosaïque germinale est. un événement rare mais probablement sous-estimé du fait de l'accès limité aux cellules germinales. Les variations génomiques caractéristiques de ce phénomène peuvent être des single nucleotide polymorphismes (SNPs), des copy number variations (CNVs) ou des aneuploïdies. Dans le cas des CNVs, les délétions sont plus fréquentes dans la lignée germinale paternelle tandis que les duplications sont plus fréquemment d'origine maternelle. Le risque de mosaïcisme germinal augmente avec l'âge paternel de part une augmentation du risque de SNPs associée à la division constante des cellules germinales pendant toute la vie d'un homme. Nous rapportons ici un cas de mosaïque germinale chez un donneur de spermatozoïdes ayant entraîné la survenue d'une grossesse pathologique. RÉSULTATS: Les paillettes d'un même donneur de spermatozoïdes ont été attribuées à sept couples receveurs permettant l'obtention de quatre grossesses évolutives. Pour l'une d'entre elle, l'échographie du deuxième trimestre a permis d'identifier chez le fœtus des pieds bots associés à un retard de croissance intra utérin. L'analyse par hybridation génomique comparative (CGH)-array après amniocentèse a révélé une délétion de 4 MB dans la région 7q32.1q33. Les caryotypes sanguins et les analyses par CGH-array étaient normaux chez la mère et le donneur. Cependant les profils de microsatellites ont montré une origine paternelle du chromosome délété. Une analyse par fluorescent in situ hybridization (FISH) des spermatozoïdes du donneur a révélé la présence de la même délétion dans 12% des spermatozoïdes étudiés. Etant donné le risque de retard mental associé à des remaniements chromosomiques dans cette même région, le couple a préféré interrompre la grossesse. Une amniocentèse a été réalisée pour les autres grossesse en cours et n'a retrouvé aucune anomalie. CONCLUSIONS: Plusieurs cas de mosaïques germinales ont été rapportés mais leur fréquence réelle reste probablement sous-estimée. En effet, un mosaïcisme germinal ne peut être détecté par les techniques de cytogénétique conventionnelle sur sang. Ce cas illustre la nécessité d'un suivi en temps réel des grossesses obtenues par don de spermatozoïdes étant donné que la survenue d'une grossesse pathologique peut avoir un retentissement sur les autres grossesses issues du même donneur.

16p13.11 microduplication in 45 new patients: refined clinical significance and genotype-phenotype correlations.

BACKGROUND: The clinical significance of 16p13.11 duplications remains controversial while frequently detected in patients with developmental delay (DD), intellectual deficiency (ID) or autism spectrum disorder (ASD). Previously reported patients were not or poorly characterised. The absence of consensual recommendations leads to interpretation discrepancy and makes genetic counselling challenging. This study aims to decipher the genotype-phenotype correlations to improve genetic counselling and patients' medical care. METHODS: We retrospectively analysed data from 16 013 patients referred to 12 genetic centers for DD, ID or ASD, and who had a chromosomal microarray analysis. The referring geneticists of patients for whom a 16p13.11 duplication was detected were asked to complete a questionnaire for detailed clinical and genetic data for the patients and their parents. RESULTS: Clinical features are mainly speech delay and learning disabilities followed by ASD. A significant risk of cardiovascular disease was noted. About 90% of the patients inherited the duplication from a parent. At least one out of four parents carrying the duplication displayed a similar phenotype to the propositus. Genotype-phenotype correlations show no impact of the size of the duplicated segment on the severity of the phenotype. However, NDE1 and miR-484 seem to have an essential role in the neurocognitive phenotype. CONCLUSION: Our study shows that 16p13.11 microduplications are likely pathogenic when detected in the context of DD/ID/ASD and supports an essential role of NDE1 and miR-484 in the neurocognitive phenotype. Moreover, it suggests the need for cardiac evaluation and follow-up and a large study to evaluate the aortic disease risk.

15q24.1 BP4-BP1 microdeletion unmasking paternally inherited functional polymorphisms combined with distal 15q24.2q24.3 duplication in a patient with epilepsy, psychomotor delay, overweight, ventricular arrhythmia.

15q24 microdeletion and microduplication syndromes are genetic disorders caused by non-allelic homologous recombination between low-copy repeats (LCRs) in the 15q24 chromosome region. Individuals with 15q24 microdeletion and microduplication syndromes share a common 1.2 Mb critical interval, spanning from LCR15q24B to LCR15q24C. Patients with 15q24 microdeletion syndrome exhibit distinct dysmorphic features, microcephaly, variable developmental delay, multiples congenital anomalies while individuals with reciprocal 15q24 microduplication syndrome show mild developmental delay, facial dysmorphism associated with skeletal and genital abnormalities. We report the first case of a 10 year-old girl presenting mild developmental delay, psychomotor retardation, epilepsy, ventricular arrhythmia, overweight and idiopathic central precocious puberty. 180K array-CGH analysis identified a 1.38 Mb heterozygous interstitial 15q24.1 BP4-BP1 microdeletion including HCN4 combined with a concomitant 2.6 Mb heterozygous distal 15q24.2q24.3 microduplication. FISH analysis showed that both deletion and duplication occurred de novo in the proband. Of note, both copy number imbalances did not involve the 1.2 Mb minimal deletion/duplication critical interval of the 15q24.1q24.2 chromosome region (74.3-75.5 Mb). Sequencing of candidate genes for epilepsy and obesity showed that the proband was hemizygous for paternal A-at risk allele of BBS4 rs7178130 and NPTN rs7171755 predisposing to obesity, epilepsy and intellectual deficits. Our study highlights the complex interaction of functional polymorphisms and/or genetic variants leading to variable clinical manifestations in patients with submicroscopic chromosomal aberrations.

First prenatal case of proximal 19p13.12 microdeletion syndrome: New insights and new delineation of the syndrome.

Proximal 19p13.12 microdeletion has been rarely reported. Only five postnatal cases with intellectual disability, facial dysmorphism, branchial arch defects and overlapping deletions involving proximal 19p13.12 have been documented. Two critical intervals were previously defined: a 700 kb for branchial arch defects and a 350 kb for hypertrichosis-synophrys-protruding front teeth. We describe the first prenatal case, a fetal death in utero at 39 weeks of gestation. Agilent 180K array-CGH analysis identified a heterozygous interstitial 745 kb deletion at 19p13.12 chromosome region, encompassing both previously reported critical intervals, including at least 6 functionally relevant genes: NOTCH3, SYDE1, AKAP8, AKAP8L, WIZ and BRD4. Quantitative PCR showed that the deletion occurred de novo with a median size of 753 kb. NOTCH3 and SYDE1 were candidate genes for placental pathology whilst AKAP8, AKAP8L, WIZ and BRD4 were highly expressed in the branchial arches. Molecular characterization and sequencing of candidate genes for placental pathology and branchial arch defects were carried out in order to correlate the genotype-phenotype relationship and unravel the underlying mechanism of proximal 19p13.12 microdeletion syndrome. This case also contributes to define the novel critical interval and expand the clinical phenotype spectrum of proximal 19p13.12 microdeletion syndrome.

Prenatal diagnosis of isochromosome 20q in a fetus with vertebral anomaly and rocker-bottom feet.

OBJECTIVE: Isochromosome of the long arm of chromosome 20 (i(20q)) is a rare structural abnormality in prenatal diagnosis. Thirty prenatal cases of mosaic i(20q) have been reported, among which only four are associated with fetal malformations. We describe a new prenatal case of i(20q) with fetal malformations. MATERIALS AND METHODS: We also observed a discrepancy between uncultured and cultured amniotic fluid cells by using conventional cytogenetic, fluorescence in situ hybridization and array-SNP analysis. RESULTS: The short arm deletion of chromosome 20 arising from the isochromosome encompassed two candidate genes PAX1 and JAG1 involved in cranio-facial and vertebral development. CONCLUSION: The data would allow establishing a phenotype-genotype correlation. Thus, we proposed to define a recognizable syndrome combining cranio-facial dysmorphism, vertebral bodies' anomalies, feet and cerebral malformations.

A French multicenter study of over 700 patients with 22q11 deletions diagnosed using FISH or aCGH.

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.

Growth hormone deficiency and pituitary malformation in a recurrent Cat-Eye syndrome: a family report.

Growth hormone deficiency affects roughly between one in 3000 and one in 4000 children with most instances of growth hormone deficiency being idiopathic. Growth hormone deficiency can also be associated with genetic diseases or chromosome abnormalities. Association of growth hormone deficiency together with hypothalamic-pituitary axis malformation and Cat-Eye syndrome is a very rare condition. We report a family with two brothers presenting with growth delay due to a growth hormone deficiency associated with a polymalformation syndrome. They both displayed pre-auricular pits and tags, imperforate anus and Duane retraction syndrome. Both parents and a third unaffected son displayed normal growth pattern. Cerebral MRI showed a hypothalamic-pituitary axis malformation in the two affected brothers. Cytogenetic studies revealed a type I small supernumerary marker chromosome derived from chromosome 22 resulting in a tetrasomy 22pter-22q11.21 characteristic of the Cat-Eye syndrome. The small supernumerary marker chromosome was present in the two affected sons and the mother in a mosaic state. Patients with short stature due to growth hormone deficiency should be evaluated for chromosomal abnormality. Family study should not be underestimated.

Azoospermia and trisomy 18p syndrome: a fortuitous association? A patient report and a review of the literature.

Complete, isolated trisomy of the short arm of chromosome 18 is very rare. To date, only 24 cases of trisomy 18p have been reported in the literature, making it difficult to define a potentially associated phenotype. However, the available evidence suggests that few clinical features are shared by these patients: only variable intellectual disability, variable facial dysmorphism and epilepsy are reported in a few patients. Although three inherited cases of trisomy 18p have already been reported, all were of maternal origin. We report on a patient carrying an isolated complete trisomy 18p translocated to the short arm of chromosome 14 and presenting with facial dysmorphism, mild intellectual disability and non-obstructive azoospermia. Chromosomal abnormalities are more frequent in infertile men with poor sperm quality than the general population. Both numerical and structural chromosomal aberrations have been already reported within the context of azoospermia. To our knowledge, this is the first patient with trisomy 18p to present a fertility impairment due to totally altered spermatogenesis and azoospermia. Although fertility disorders were not mentioned in the four previous reports of men with trisomy 18p, none of the latter had children. We suggest that azoospermia is a previously uncharacterized feature of trisomy 18p syndrome. We further hypothesize that two mechanisms could be responsible of the fertility impairment: a meiotic synapsis defect due to the additional 18p arm that blocks meiosis, and/or overexpression of a gene located on the 18p chromosome involved in the normal testicular development.

Severe psychomotor delay in a severe presentation of cat-eye syndrome.

Cat-eye syndrome is a rare genetic syndrome of chromosomal origin. Individuals with cat-eye syndrome are characterized by the presence of preauricular pits and/or tags, anal atresia, and iris coloboma. Many reported cases also presented with variable congenital anomalies and intellectual disability. Most patients diagnosed with CES carry a small supernumerary bisatellited marker chromosome, resulting in partial tetrasomy of 22p-22q11.21. There are two types of small supernumerary marker chromosome, depending on the breakpoint site. In a very small proportion of cases, other cytogenetic anomalies are reportedly associated with the cat-eye syndrome phenotype. Here, we report a patient with cat-eye syndrome caused by a type 1 small supernumerary marker chromosome. The phenotype was atypical and included a severe developmental delay. The use of array comparative genomic hybridization ruled out the involvement of another chromosomal imbalance in the neurological phenotype. In the literature, only a few patients with cat-eye syndrome present with a severe developmental delay, and all of the latter carried an atypical partial trisomy 22 or an uncharacterized small supernumerary marker chromosome. Hence, this is the first report of a severe neurological phenotype in cat-eye syndrome with a typical type 1 small supernumerary marker chromosome. Our observation clearly complicates prognostic assessment, particularly when cat-eye syndrome is diagnosed prenatally.

Clinical and molecular characterization of the 20q11.2 microdeletion syndrome: six new patients.

Interstitial microdeletions of 20q chromosome are rare, only 17 patients have been reported in the literature to date. Among them, only six carried a proximal 20q11.21-q11.23 deletion, with a size ranging from 2.6 to 6.8 Mb. The existence of a 20q11.2 microdeletion syndrome has been proposed, based on five previously reported cases that displayed anomalies of the extremities, intellectual disability, feeding difficulties, craniofacial dysmorphism and variable malformations. To further characterize this syndrome, we report on six new patients with 20q11.2 microdeletions diagnosed by whole-genome array-based comparative genomic hybridization. These patient reports more precisely refined the phenotype and narrowed the minimal critical region involved in this syndrome. Careful clinical assessment confirms the distinctive clinical phenotype. The craniofacial dysmorphism consists of high forehead, frontal bossing, enophthalmos, and midface hypoplasia. We have identified a 1.62 megabase minimal critical region involved in this syndrome encompassing three genes­GDF5, EPB41L1, andSAMHD1­which are strong candidates for different aspects of the phenotype. These results support that 20q11.2 microdeletion syndrome is a new contiguous gene deletion syndrome with a recognizable phenotype.

Involvement of interstitial telomeric sequences in two new cases of mosaicism for autosomal structural rearrangements.

Mosaicism for an autosomal structural rearrangement that does not involve ring or marker chromosomes is rare. The mechanisms responsible for genome instability have not always been explained. Several studies have shown that interstitial telomeric sequences (ITSs), involved in some mosaic constitutional anomalies, are potent sources of genomic instability. Here we describe two cases of mosaicism for uncommon constitutional autosomal rearrangements, involving ITSs, identified by karyotyping and characterized by FISH and SNP-array analysis. The first patient, a boy with global developmental delay, had a rare type of pure distal 1q inverted duplication (1q32-qter), attached to the end of the short arm of the same chromosome 1, in approximately 35% of his cells. The second patient, a phenotypically normal man, was diagnosed as having mosaic for a balanced non-reciprocal translocation of the distal segment of 7q (7q33qter), onto the terminal region of the short arm of a whole chromosome 12, in approximately 80% of his cells. The remaining 20% of the cells showed an unbalanced state of the translocation, with only the der(7) chromosome. He was ascertained through his malformed fetus carrying a non-mosaic partial monosomy 7q, identified at prenatal diagnosis. We show that pan-telomeric and subtelomeric sequences were observed at the interstitial junction point of the inv dup(1q) and of the der(12)t(7;12), respectively. The present cases and review of the literature suggest that the presence of ITSs at internal sites of the chromosomes may explain mechanisms of the patients's mosaic structural rearrangements.