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Purpose: Progressive inherited retinal degenerations (IRDs) affecting rods and cones are clinically and genetically heterogeneous and can lead to blindness with limited therapeutic options. The major gene defects have been identified in subjects of European and Asian descent with only few reports of North African descent., Methods: Genome, targeted next-generation, and Sanger sequencing was applied to cohort of ∼4000 IRDs cases. Expression analyses were performed including Chip-seq database analyses, on human-derived retinal organoids (ROs), retinal pigment epithelium cells, and zebrafish. Variants' pathogenicity was accessed using 3D-modeling and/or ROs., Results: Here, we identified a novel gene defect with three distinct pathogenic variants in UBAP1L in 4 independent autosomal recessive IRD cases from Tunisia. UBAP1L is expressed in the retinal pigment epithelium and retina, specifically in rods and cones, in line with the phenotype. It encodes Ubiquitin-associated protein 1-like, containing a solenoid of overlapping ubiquitin-associated domain, predicted to interact with ubiquitin. In silico and in vitro studies, including 3D-modeling and ROs revealed that the solenoid of overlapping ubiquitin-associated domain is truncated and thus ubiquitin binding most likely abolished secondary to all variants identified herein., Conclusion: Biallelic UBAP1L variants are a novel cause of IRDs, most likely enriched in the North African population., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The SMARCC1 gene has been involved in congenital ventriculomegaly with aqueduct stenosis but only a few patients have been reported so far, with no antenatal cases, and it is currently not annotated as a morbid gene in OMIM nor in the Human Phenotype Ontology. Most of the reported variants are loss of function (LoF) and are often inherited from unaffected parents. SMARCC1 encodes a subunit of the mSWI/SNF complex and affects the chromatin structure and expression of several genes. Here, we report the two first antenatal cases of SMARCC1 LoF variants detected by Whole Genome Sequencing (WGS). Ventriculomegaly is the common feature in those fetuses. Both identified variants are inherited from a healthy parent, which supports the reported incomplete penetrance of this gene. This makes the identification of this condition in WGS as well as the genetic counseling challenging., Competing Interests: Declaration of competing interest The authors declare no potential conflict of interest., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

17-ß Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is an enzyme transforming Delta 4 androstenedione into testosterone. It is involved in the early development of the male genital tract. In this case report, we describe a 46,XY Difference of Sexual Development (DSD) individual with a female phenotype, primary amenorrhea, facial dysmorphia and mental retardation. Gene sequencing using a panel of genes involved in DSD revealed two heterozygous loss-of-function mutations in the HSD17B3 enzyme. Furthermore, a microarray analysis revealed a 37Mb segmental 3p duplication and a recurrent 16p13.11 microduplication. The large 3p duplication is responsible for her mental retardation and her facial dysmorphia. Interestingly, HSD17B3 mutations were identified only in adulthood, at the age of 49. Furthermore, the patient's severe mental retardation and facial dysmorphia are due to genetic abnormalities different from the ones involved in her DSD., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Purpose: Abnormality of the corpus callosum (AbnCC) is etiologically a heterogeneous condition and the prognosis in prenatally diagnosed cases is difficult to predict. The purpose of our research was to establish the diagnostic yield using chromosomal microarray (CMA) and exome sequencing (ES) in cases with prenatally diagnosed isolated (iAbnCC) and nonisolated AbnCC (niAbnCC)., Methods: CMA and prenatal trio ES (pES) were done on 65 fetuses with iAbnCC and niAbnCC. Only pathogenic gene variants known to be associated with AbnCC and/or intellectual disability were considered., Results: pES results were available within a median of 21.5 days (9-53 days). A pathogenic single-nucleotide variant (SNV) was identified in 12 cases (18%) and a pathogenic CNV was identified in 3 cases (4.5%). Thus, the genetic etiology was determined in 23% of cases. In all diagnosed cases, the results provided sufficient information regarding the neurodevelopmental prognosis and helped the parents to make an informed decision regarding the outcome of the pregnancy., Conclusion: Our results show the significant diagnostic and prognostic contribution of CMA and pES in cases with prenatally diagnosed AbnCC. Further prospective cohort studies with long-term follow-up of the born children will be needed to provide accurate prenatal counseling after a negative pES result.

Chromoanagenesis represents an extreme form of genomic rearrangements involving multiple breaks occurring on a single or multiple chromosomes. It has been recently described in both acquired and rare constitutional genetic disorders. Constitutional chromoanagenesis events could lead to abnormal phenotypes including developmental delay and congenital anomalies, and have also been implicated in some specific syndromic disorders. We report the case of a girl presenting with growth retardation, hypotonia, microcephaly, dysmorphic features, coloboma, and hypoplastic corpus callosum. Karyotype showed a de novo structurally abnormal chromosome 14q31qter region. Molecular characterization using SNP-array revealed a complex unbalanced rearrangement in 14q31.1-q32.2, on the paternal chromosome 14, including thirteen interstitial deletions ranging from 33 kb to 1.56 Mb in size, with a total of 4.1 Mb in size, thus suggesting that a single event like chromoanagenesis occurred. To our knowledge, this is one of the first case of 14q distal deletion due to a germline chromoanagenesis. Genome sequencing allowed the characterization of 50 breakpoints, leading to interruption of 10 genes including YY1 which fit with the patient's phenotype. This precise genotyping of breaking junction allowed better definition of genotype-phenotype correlations., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Purpose: To investigate the genetic basis of congenital ataxias (CAs), a unique group of cerebellar ataxias with a nonprogressive course, in 20 patients from consanguineous families, and to identify new CA genes., Methods: Singleton -exome sequencing on these 20 well-clinically characterized CA patients. We first checked for rare homozygous pathogenic variants, then, for variants from a list of genes known to be associated with CA or very early-onset ataxia, regardless of their mode of inheritance. Our replication cohort of 180 CA patients was used to validate the new CA genes., Results: We identified a causal gene in 16/20 families: six known CA genes (7 patients); four genes previously implicated in another neurological phenotype (7 patients); two new candidate genes (2 patients). Despite the consanguinity, 4/20 patients harbored a heterozygous de novo pathogenic variant., Conclusion: Singleton exome sequencing in 20 consanguineous CA families led to molecular diagnosis in 80% of cases. This study confirms the genetic heterogeneity of CA and identifies two new candidate genes (PIGS and SKOR2). Our work illustrates the diversity of the pathophysiological pathways in CA, and highlights the pathogenic link between some CA and early infantile epileptic encephalopathies related to the same genes (STXBP1, BRAT1, CACNA1A and CACNA2D2).

Xp21 continuous gene deletion syndrome is characterized by complex glycerol kinase deficiency (GK), adrenal hypoplasia congenital (NROB1), intellectual disability and/or Duchenne muscular dystrophy (DMD). The clinical features depend on the size of the deletion, as well as on the number and the nature of the encompassed genes. More than 100 male patients have been reported so far, while only a few cases of symptomatic female carriers have been described. We report here detailed clinical features and X chromosome inactivation analysis in two unrelated female patients with overlapping Xp21 deletions presenting with intellectual disability and inconstant muscular symptoms., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Beckwith-Wiedemann syndrome is an overgrowth disorder with an increased risk of childhood tumors that results from a dysregulation of imprinted gene expression in the 11p15 region. Since epigenetic defects are the most frequent anomalies, first-line diagnostic methods involve methylation analysis. When paternal isodisomy is suspected, it should be confirmed by a second technique capable of distinguishing true 11p15 paternal disomy (patUPD) from paternal 11p15 duplication or 11p15 trisomy. We sought to evaluate the interest of using SNP arrays in the Beckwith-Wiedemann syndrome diagnostic strategy. We analyzed the SNP profiles of 25 Beckwith Wiedemann patients with previously determined methylation indexes. Among them, 3 had 11p15 trisomies, 13 had patUPD, 8 had an inconclusive methylation index and 1 had a normal result. All known trisomies and known patUPDs were detected. Moreover we found 7 low-rate mosaicisms 11p15 patUPDs among the 8 patients with an inconclusive methylation index. We were able to precisely characterize the sizes and mosaicism rates of the anomalies. We demonstrate that SNP arrays are of real diagnostic interest in Beckwith-Wiedemann syndrome: 1) they help to distinguish patUPDs from trisomies more precisely than karyotyping and FISH, 2) they help determine the size and mosaicism rate of patUPDs, 3) they provide complementary information in inconclusive cases, helping to distinguish low-rate patUPD mosaicism from other BWS-related molecular defects., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Spontaneous fertility is rare among patients with Turner syndrome and is most likely in women with mosaicism for a normal 46,XX cell line. We report an unusual case of familial Turner syndrome with mosaicism for a novel X;Y translocation involving Xp and Yp. The chromosomal analysis was carried out through cytogenetics and molecular karyotyping using a SNP array platform. The mother, a Turner syndrome woman, diagnosed in midchildhood because of short stature, was found to have a 45,X/46,X,der(X)t(X;Y)(p11.4;p11.2) karyotype, with a predominant 45,X cell line. Her parents decided against prophylactic gonadectomy, generally recommended at an early age when Y chromosome has been identified, because at age 13, she had spontaneous puberty and menarche. She reached a final height of 154 cm after treatment with growth hormone. At age 24, she became spontaneously pregnant. She had a mild aortic coarctation and close follow-up cardiac evaluation, including cardiac magnetic resonance imaging, had been performed during her pregnancy, which progressed uneventfully, except for intra-uterine growth retardation. Prenatal diagnosis revealed a female karyotype, with transmission of the maternal translocation with an unexpected different mosaic:47,X,der(X)t(X;Y)x2/46,X,der(X)t(X;Y) karyotype. This complex and unusual karyotype, including a mosaic partial trisomy X and a non-mosaic Xpter-Xp11.4 monosomy, results in transmission of Turner syndrome from mother to daughter. At birth, the girl had normal physical examination except for growth retardation. This family illustrates the complexity and difficulties, in term of patient counseling and management in Turner syndrome, in determining ovarian status, fertility planning, risks associated with pregnancies, particularly when mosaicism for Y material chromosome is identified., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Klinefelter syndrome is defined by the presence of a supernumerary X chromosome in a phenotypic male. It is the most frequent gonosomic anomaly in infertile men with an incidence of 0.1 to 0.2% in newborn males. The presence of an additional X chromosome induces spermatogenic failure but when gametes are present, they are usually normal. The risk of transmission of the chromosomal anomaly remains low. In the literature, only one 47,XXY foetus resulting from more than a hundred births from fathers with Klinefelter syndrome, has been reported. One can estimate, that a TESE performed in half of the patients with non-mosaic 47,XXY will be positive and may enable IVF/ICSI to be achieved., (Copyright © 2011. Published by Elsevier SAS.)

Submicroscopic duplications of the genomic interval deleted in Miller-Dieker syndrome (MDS) were recently identified by array-based comparative genomic hybridization (a-CGH) studies, describing new genomic disorders in the MDS locus. These rearrangements of varying size, from 59-88 kb to 4 Mb, were non-recurrent, and appear to result from diverse molecular mechanisms. Only five patients had overlapping 17p13.3 duplications including the entire MDS critical region. We describe here a 13-year-old girl with a novel microduplication of the MDS critical region, involving the PAFAH1B1 and YWHAE genes. She presented with moderate psychomotor retardation, speech delay, behavioral problems, and bilateral cleft lip and palate, a previously unreported manifestation. Initially diagnosed as having an apparently simple terminal Xq26 deletion on standard cytogenetic analysis, she was found to have an associated terminal 4.2 Mb 17p13.3 submicroscopic duplication, identified by subtelomere FISH analysis, further characterized by high-resolution array CGH, resulting from an unbalanced X;17 translocation. Phenotypic comparison with the 5 other patients previously described, revealed common phenotypic features, such as hypotonia, mild to moderate developmental delay/mental retardation, speech abnormalities, behavioral problems, recurrent infections, relatively increase of body weight, discrete facial dysmorphism including downslanting palpebral fissures, broad midface, pointed chin, contributing to further delineate this new 17p13.3 microduplication syndrome., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Hypogonadotrophic hypogonadism (HH) is characterized by deficient gonadotrophin secretion, resulting from pituitary or hypothalamic defects. In order to induce spermatogenesis, HH patients are treated with commercially available gonadotrophins. As far as is known, quality and genetic integrity of induced sperm cells have never been investigated, although they represent an important issue, since the ultimate goal of this treatment is to have competent spermatozoa in order to achieve paternity. In order to evaluate the nuclear integrity of induced sperm cells, sperm samples from treated HH patients were compared with sperm samples from normospermic control donors. Sperm cells were analysed by fluorescence in-situ hybridization, using probes specific for chromosomes 13, 21, 18, X and Y, and by TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labelling assay. Results showed that the rate of aneuploid and diploid sperm cells in patients was not statistically different from controls and that the rate of sperm cells with fragmented DNA was within the normal values. Spermatozoa obtained by gonadotrophin treatment in HH patients are likely to have a balanced chromosomal content and a normal DNA integrity but this conclusion needs to be confirmed by further studies dealing with a greater number of patients., (Copyright © 2010 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: Maternally derived duplications of the 15q11-q13 region are the most frequently reported chromosomal aberrations in autism spectrum disorders (ASD). Prader-Willi and Angelman syndromes, caused by 15q11-q13 deletions or abnormal methylation of imprinted genes, are also associated with ASD. However, the prevalence of these disorders in ASD is unknown. The aim of this study was to assess the frequency of 15q11-q13 rearrangements in a large sample of patients ascertained for ASD., Methods: A total of 522 patients belonging to 430 families were screened for deletions, duplications, and methylation abnormalities involving 15q11-q13 with multiplex ligation-dependent probe amplification (MLPA)., Results: We identified four patients with 15q11-q13 abnormalities: a supernumerary chromosome 15, a paternal interstitial duplication, and two subjects with Angelman syndrome, one with a maternal deletion and the other with a paternal uniparental disomy., Conclusions: Our results show that abnormalities of the 15q11-q13 region are a significant cause of ASD, accounting for approximately 1% of cases. Maternal interstitial 15q11-q13 duplications, previously reported to be present in 1% of patients with ASD, were not detected in our sample. Although paternal duplications of chromosome 15 remain phenotypically silent in the majority of patients, they can give rise to developmental delay and ASD in some subjects, suggesting that paternally expressed genes in this region can contribute to ASD, albeit with reduced penetrance compared with maternal duplications. These findings indicate that patients with ASD should be routinely screened for 15q genomic imbalances and methylation abnormalities and that MLPA is a reliable, rapid, and cost-effective method to perform this screening.

Cytogenetic investigations are performed in couples asking for IVF or intracytoplasmic sperm injection (ICSI) treatment. These serve a diagnostic purpose because male or female infertility might have a chromosomal origin. Chromosomal aberrations found in these patients include numerical abnormalities, such as Klinefelter syndrome, XYY karyotype or Turner syndrome and its variants; sex reversions, such as XX males or XY females; and also structural abnormalities, such as Robertsonian or reciprocal translocations and inversions. Finding the chromosomal origin of infertility in a patient also has a prognostic value because it aids the management of pregnancies obtained after IVF or ICSI and may lead to a proposal of prenatal or preimplantation genetic diagnosis.

Molecular anomalies of the Y chromosome leading to male infertility are mainly microdeletions of the long arm of the Y chromosome. Three recurrently deleted portions of the long arm are the AZFa, AZFb and AZFc (AZF: Azoospermia Factor) regions. Complete deletions of the AZFc region are found in 10% of cases of severe male infertility. In addition to the AZF deletions, certain classes of Y chromosome (haplogroups) may also predispose to male infertility and could be transmitted to future male descents by various Assisted Reproductive Techniques (ART). Since the first discovery of microdeletions, the sequence of the Y chromosome has become available, revealing the mechanisms underlying deletion formation and also resulting in a coherent screening strategy. Recently, partial deletions of the AZF regions have been described. The significance of these deletions in the clinical context remains to be defined.

Two new patients, mosaic for a small supernumerary ring chromosome 7 are described. There are only seven published reported concerning supernumerary ring chromosome 7 and we reviewed the previously reported cases in an attempt to establish genotype-phenotype correlations, which are particularly important for genetic counselling and clinical genetics. Our first case was a 20 months old girl who was referred for a mild motor developmental delay, an asymmetric facial appearance, a plagiocephaly and a short nose with anteverted nostrils. Our second case was a 9 years old boy who was referred for a IQ at the lower end of the normal range (? 80), obesity, hyperactivity and some dysmorphic features including hypertelorism and down slanting palpebral fissures. In both cases, chromosome analysis after G and R banding and FISH showed a small ring chromosome 7 in respectively 76% and 50% of consecutively scored metaphases. Both ring chromosomes were labelled by FISH using the Williams Syndrome locus probe (Elastin Gene D7S486). Comparison between these two cases and previously published cases allowed to delineate frequent clinical findings. A mild mental retardation was found in the majority of patients. which is an important data for genetic counselling.

Testis determination is the complex process by which the bipotential gonad becomes a normal testis during embryo development. As a consequence, this process leads to sexual differentiation corresponding to the masculinization of both genital track and external genitalia. The whole phenomenon is under genetic control and is particularly driven by the presence of the Y chromosome and by the SRY gene, which acts as the key initiator of the early steps of testis determination. However, many other autosomal genes, present in both males and females, are expressed during testis formation in a gene activation pathway, which is far to be totally elucidated. All these genes act in a dosage-sensitive manner by which quantitative gene abnormalities, due to chromosomal deletions, duplications or mosaicism, may lead to testis determination failure and sex reversal.

Human spermatogenesis failures appear frequently as idiopathic and may be due to genetic causes. Mutations of genes involved in the hypothalamic/pituitary control of spermatogenesis have been described and account for several types of hypogonadotropic hypogonadism. Chromosomal abnormalities found in infertile patients are either gonosomal aneuploidies or structural anomalies which interfere with the normal chromosome behaviour at meiosis and lead to germ cell breakdown. Microdeletions of the Y chromosome are often undetectable at karyotype and are responsible for the loss of genes which compose the AZF factor. The increase in the number of mouse models of infertility will allow the description of many human genes involved in the spermatogenesis process provided that a detailed analysis of their genotype-phenotype relationships is performed.

This prospective and multi-centric study confirms the accuracy and the limitations of interphase FISH and shows that any cytogenetics laboratory can perform this technique. With regard to the technical approach, we think that slides must be examined by two investigators, because the scoring may be subjective. The main problem with the AneuVysion kit concerns the alpha satellite probes, and especially the chromosome 18 probe, which is sometimes very difficult to interpret because of the high variability of the size of the spots, and this may lead to false negative and uninformative cases. The best solution would be to replace these probes by locus-specific probes. Concerning clinical management, we offer interphase FISH only in very high-risk pregnancies or/and at late gestational age because of the cost of the test. We think that an aberrant FISH result can be used for a clinical decision when it is associated with a corresponding abnormal ultrasound scan. In other cases, most of the time, we prefer to wait for the standard karyotype.