Multiple molecular diagnoses in the field of intellectual disability and congenital anomalies: 3.5% of all positive cases.

PURPOSE: Wide access to clinical exome/genome sequencing (ES/GS) enables the identification of multiple molecular diagnoses (MMDs), being a long-standing but underestimated concept, defined by two or more causal loci implicated in the phenotype of an individual with a rare disease. Only few series report MMDs rates (1.8% to 7.1%). This study highlights the increasing role of MMDs in a large cohort of individuals addressed for congenital anomalies/intellectual disability (CA/ID). METHODS: From 2014 to 2021, our diagnostic laboratory rendered 880/2658 positive ES diagnoses for CA/ID aetiology. Exhaustive search on MMDs from ES data was performed prospectively (January 2019 to December 2021) and retrospectively (March 2014 to December 2018). RESULTS: MMDs were identified in 31/880 individuals (3.5%), responsible for distinct (9/31) or overlapping (22/31) phenotypes, and potential MMDs in 39/880 additional individuals (4.4%). CONCLUSION: MMDs are frequent in CA/ID and remain a strong challenge. Reanalysis of positive ES data appears essential when phenotypes are partially explained by the initial diagnosis or atypically enriched overtime. Up-to-date clinical data, clinical expertise from the referring physician, strong interactions between clinicians and biologists, and increasing gene discoveries and improved ES bioinformatics tools appear all the more fundamental to enhance chances of identifying MMDs. It is essential to provide appropriate patient care and genetic counselling.

Low risk of embryonic and other cancers in PIK3CA-related overgrowth spectrum: Impact on screening recommendations.

The PIK3CA-related overgrowth spectrum (PROS) encompasses various conditions caused by mosaic activating PIK3CA variants. PIK3CA somatic variants are also involved in various cancer types. Some generalized overgrowth syndromes are associated with an increased risk of Wilms tumor (WT). In PROS, abdominal ultrasound surveillance has been advocated to detect WT. We aimed to determine the risk of embryonic and other types of tumors in patients with PROS in order to evaluate surveillance relevance. We searched the clinical charts from 267 PROS patients for the diagnosis of cancer, and reviewed the medical literature for the risk of cancer. In our cohort, six patients developed a cancer (2.2%), and Kaplan Meier analyses estimated cumulative probabilities of cancer occurrence at 45 years of age was 5.6% (95% CI = 1.35%-21.8%). The presence of the PIK3CA variant was only confirmed in two out of four tumor samples. In the literature and our cohort, six cases of Wilms tumor/nephrogenic rests (0.12%) and four cases of other cancers have been reported out of 483 proven PIK3CA patients, in particular the p.(His1047Leu/Arg) variant. The risk of WT in PROS being lower than 5%, this is insufficient evidence to recommend routine abdominal imaging. Long-term follow-up studies are needed to evaluate the risk of other cancer types, as well as the relationship with the extent of tissue mosaicism and the presence or not of the variant in the tumor samples.

The neurodevelopmental and facial phenotype in individuals with a TRIP12 variant.

Haploinsufficiency of TRIP12 causes a neurodevelopmental disorder characterized by intellectual disability associated with epilepsy, autism spectrum disorder and dysmorphic features, also named Clark-Baraitser syndrome. Only a limited number of cases have been reported to date. We aimed to further delineate the TRIP12-associated phenotype and objectify characteristic facial traits through GestaltMatcher image analysis based on deep-learning algorithms in order to establish a TRIP12 gestalt. 38 individuals between 3 and 66 years (F = 20, M = 18) - 1 previously published and 37 novel individuals - were recruited through an ERN ITHACA call for collaboration. 35 TRIP12 variants were identified, including frameshift (n = 15) and nonsense (n = 6) variants, as well as missense (n = 5) and splice (n = 3) variants, intragenic deletions (n = 4) and two multigene deletions disrupting TRIP12. Though variable in severity, global developmental delay was noted in all individuals, with language deficit most pronounced. About half showed autistic features and susceptibility to obesity seemed inherent to this disorder. A more severe expression was noted in individuals with a missense variant. Facial analysis showed a clear gestalt including deep-set eyes with narrow palpebral fissures and fullness of the upper eyelids, downturned corners of the mouth and large, often low-set ears with prominent earlobes. We report the largest cohort to date of individuals with TRIP12 variants, further delineating the associated phenotype and introducing a facial gestalt. These findings will improve future counseling and patient guidance.

1p36 deletion syndrome: Review and mapping with further characterization of the phenotype, a new cohort of 86 patients.

Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American population), due to a heterozygous deletion of part of the short arm of chromosome 1. The 1p36DS is characterized by typical craniofacial features, developmental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenital heart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature. The aim of our study was to (1) evaluate the incidence of the 1p36DS in the French population compared to 22q11.2 deletion syndrome and trisomy 21; (2) review the postnatal phenotype related to microarray data, compared to previously publish prenatal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiens de Langue Française), we have collected data of 86 patients constituting, to the best of our knowledge, the second-largest cohort of 1p36DS patients in the literature. We estimated an average of at least 10 cases per year in France. 1p36DS seems to be much less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients presented mainly dysmorphism, microcephaly, developmental delay/intellectual disability, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy, or cardiovascular malformations and, pre and/or postnatal growth retardation. Cardiac abnormalities, brain malformations, and epilepsy were more frequent in distal deletions, whereas microcephaly was more common in proximal deletions. Mapping and genotype-phenotype correlation allowed us to identify four critical regions responsible for intellectual disability. This study highlights some phenotypic variability, according to the deletion position, and helps to refine the phenotype of 1p36DS, allowing improved management and follow-up of patients.

New insights into CC2D2A-related Joubert syndrome.

PURPOSE: In this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes, CC2D2A. METHODS: We selected 53 patients with pathogenic variants on CC2D2A, compiled and analysed their clinical, neuroimaging and genetic information and compared it to previous literature. RESULTS: Developmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype-phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype. CONCLUSION: This study contradicts previous literature stating an association between CC2D2A-related JS and ventriculomegaly. Our study implies that CC2D2A-related JS is linked to positive neurodevelopmental outcome and low rate of other organ defects except for homozygous pathogenic variant p.Arg950*. This information will help modulate patient follow-up and provide families with accurate genetic counselling.

Exome sequencing as a first-tier test for copy number variant detection: retrospective evaluation and prospective screening in 2418 cases.

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

Rapid exome sequencing in critically ill infants: implementation in routine care from French regional hospital's perspective.

This monocentric study included fifteen children under a year old in intensive care with suspected monogenic conditions for rapid trio exome sequencing (rES) between April 2019 and April 2021. The primary outcome was the time from blood sampling to rapid exome sequencing report to parents. All results were available within 16 days and were reported to parents in or under 16 days in 13 of the 15 individuals (86%). Six individuals (40%) received a diagnosis with rES, two had a genetic condition not diagnosed by rES. Eight individuals had their care impacted by their rES results, four were discharged or died before the results. This small-scale study shows that rES can be implemented in a regional University hospital with rapid impactful diagnosis to improve care in critically ill infants.

Extending the prenatal Noonan's phenotype by review of ultrasound and autopsy data.

OBJECTIVES: The antenatal phenotypic spectrum of Noonan Syndrome (NS) requires better characterization. METHODS: This multicenter retrospective observational included 16 fetuses with molecularly confirmed NS admitted for fetopathological examination between 2009 and 2016. RESULTS: Among 12 pathogenic variants (PV) in PTPN11 (80%), 5 (42%) fell between position c.179 and c.182. Ultrasound showed increased nuchal translucency (n = 13/16, 93%), increased nuchal fold after 15 weeks of gestation (n = 12/16, 75%), pleural effusions (n = 11/16, 69%), polyhydramnios (n = 9/16, 56%), hydrops (n = 7/16, 44%), cardiovascular (n = 6/16, 38%) and cerebral (n = 4/16, 25%) anomalies. Fetopathological examination found dysmorphic features in all cases, cardiovascular anomalies (n = 12/15, 80%), pulmonary hypoplasia (n = 10/15, 67%), effusions (n = 7/15, 47%) and neuropathological anomalies (n = 5/15, 33%). Hydrops was significantly (p = 0.02) more frequent in the four fetuses with RIT1, NRAS and RAF1 PV versus the 12 fetuses with PTPN11 PV. CONCLUSIONS: Increased nuchal translucency and nuchal fold is common in NS. Noonan Syndrome antenatal phenotype showed high in utero fetal death, hydrops, prenatal pleural effusion and pulmonary hypoplasia, although the inclusion of only deceased fetuses will have selected more severe phenotypes. Non-specific cardiovascular and neurological abnormalities should be added to NS antenatal phenotype. Next generation sequencing will help detect more genotypes, clarifying the prenatal phenotype and identifying genotype-phenotype correlations.

First evidence of SOX2 mutations in Peters' anomaly: Lessons from molecular screening of 95 patients.

Peters' anomaly (PA) is a rare anterior segment dysgenesis characterized by central corneal opacity and irido-lenticulo-corneal adhesions. Several genes are involved in syndromic or isolated PA (B3GLCT, PAX6, PITX3, FOXE3, CYP1B1). Some copy number variations (CNVs) have also been occasionally reported. Despite this genetic heterogeneity, most of patients remain without genetic diagnosis. We retrieved a cohort of 95 individuals with PA and performed genotyping using a combination of comparative genomic hybridization, whole genome, exome and targeted sequencing of 119 genes associated with ocular development anomalies. Causative genetic defects involving 12 genes and CNVs were identified for 1/3 of patients. Unsurprisingly, B3GLCT and PAX6 were the most frequently implicated genes, respectively in syndromic and isolated PA. Unexpectedly, the third gene involved in our cohort was SOX2, the major gene of micro-anophthalmia. Four unrelated patients with PA (isolated or with microphthalmia) were carrying pathogenic variants in this gene that was never associated with PA before. Here we described the largest cohort of PA patients ever reported. The genetic bases of PA are still to be explored as genetic diagnosis was unavailable for 2/3 of patients. Nevertheless, we showed here for the first time the involvement of SOX2 in PA, offering new evidence for its role in corneal transparency and anterior segment development.

CDK13-related disorder: Report of a series of 18 previously unpublished individuals and description of an epigenetic signature.

PURPOSE: Rare genetic variants in CDK13 are responsible for CDK13-related disorder (CDK13-RD), with main clinical features being developmental delay or intellectual disability, facial features, behavioral problems, congenital heart defect, and seizures. In this paper, we report 18 novel individuals with CDK13-RD and provide characterization of genome-wide DNA methylation. METHODS: We obtained clinical phenotype and neuropsychological data for 18 and 10 individuals, respectively, and compared this series with the literature. We also compared peripheral blood DNA methylation profiles in individuals with CDK13-RD, controls, and other neurodevelopmental disorders episignatures. Finally, we developed a support vector machine-based classifier distinguishing CDK13-RD and non-CDK13-RD samples. RESULTS: We reported health and developmental parameters, clinical data, and neuropsychological profile of individuals with CDK13-RD. Genome-wide differential methylation analysis revealed a global hypomethylated profile in individuals with CDK13-RD in a highly sensitive and specific model that could aid in reclassifying variants of uncertain significance. CONCLUSION: We describe the novel features such as anxiety disorder, cryptorchidism, and disrupted sleep in CDK13-RD. We define a CDK13-RD DNA methylation episignature as a diagnostic tool and a defining functional feature of the evolving clinical presentation of this disorder. We also show overlap of the CDK13 DNA methylation profile in an individual with a functionally and clinically related CCNK-related disorder.

Characterization of Loss-Of-Function KCNJ2 Mutations in Atypical Andersen Tawil Syndrome.

Andersen-Tawil Syndrome (ATS) is a rare disease defined by the association of cardiac arrhythmias, periodic paralysis and dysmorphic features, and is caused by KCNJ2 loss-of-function mutations. However, when extracardiac symptoms are atypical or absent, the patient can be diagnosed with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), a rare arrhythmia at high risk of sudden death, mostly due to RYR2 mutations. The identification of KCNJ2 variants in CPVT suspicion is very rare but important because beta blockers, the cornerstone of CPVT therapy, could be less efficient. We report here the cases of two patients addressed for CPVT-like phenotypes. Genetic investigations led to the identification of p. Arg82Trp and p. Pro186Gln de novo variants in the KCNJ2 gene. Functional studies showed that both variants forms of Kir2.1 monomers act as dominant negative and drastically reduced the activity of the tetrameric channel. We characterize here a new pathogenic variant (p.Pro186Gln) of KCNJ2 gene and highlight the interest of accurate cardiologic evaluation and of attention to extracardiac signs to distinguish CPVT from atypical ATS, and guide therapeutic decisions. We also confirm that the KCNJ2 gene must be investigated during CPVT molecular analysis.

Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism.

BACKGROUND: Previous research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution of protein-coding (coding) de novo variants (DNVs) within specific genes. The role of de novo noncoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2671 families with autism (discovery cohort of 516 families, replication cohort of 2155 families). We focused on DNVs in enhancers with characterized in vivo activity in the brain and identified an excess of DNVs in an enhancer named hs737. RESULTS: We adapted the fitDNM statistical model to work in noncoding regions and tested enhancers for excess of DNVs in families with autism. We found only one enhancer (hs737) with nominal significance in the discovery (p = 0.0172), replication (p = 2.5 × 10-3), and combined dataset (p = 1.1 × 10-4). Each individual with a DNV in hs737 had shared phenotypes including being male, intact cognitive function, and hypotonia or motor delay. Our in vitro assessment of the DNVs showed they all reduce enhancer activity in a neuronal cell line. By epigenomic analyses, we found that hs737 is brain-specific and targets the transcription factor gene EBF3 in human fetal brain. EBF3 is genome-wide significant for coding DNVs in NDDs (missense p = 8.12 × 10-35, loss-of-function p = 2.26 × 10-13) and is widely expressed in the body. Through characterization of promoters bound by EBF3 in neuronal cells, we saw enrichment for binding to NDD genes (p = 7.43 × 10-6, OR = 1.87) involved in gene regulation. Individuals with coding DNVs have greater phenotypic severity (hypotonia, ataxia, and delayed development syndrome [HADDS]) in comparison to individuals with noncoding DNVs that have autism and hypotonia. CONCLUSIONS: In this study, we identify DNVs in the hs737 enhancer in individuals with autism. Through multiple approaches, we find hs737 targets the gene EBF3 that is genome-wide significant in NDDs. By assessment of noncoding variation and the genes they affect, we are beginning to understand their impact on gene regulatory networks in NDDs.

Tenorio syndrome: Description of 14 novel cases and review of the clinical and molecular features.

Tenorio syndrome (TNORS) (OMIM #616260) is a relatively recent disorder with very few cases described so far. Clinical features included macrocephaly, intellectual disability, hypotonia, enlarged ventricles and autoimmune diseases. Molecular underlying mechanism demonstrated missense variants and a large deletion encompassing RNF125, a gene that encodes for an U3 ubiquitin ligase protein. Since the initial description of the disorder in six patients from four families, several new patients were diagnosed, adding more evidence to the clinical spectrum. In this article, we described 14 additional cases with deep phenotyping and make an overall review of all the cases with pathogenic variants in RNF125. Not all patients presented with overgrowth, but instead, most patients showed a common pattern of neurodevelopmental disease, macrocephaly and/or large forehead. Segregation analysis showed that, though the variant was inherited in some patients from an apparently asymptomatic parent, deep phenotyping suggested a mild form of the disease in some of them. The mechanism underlying the development of this disease is not well understood yet and the report of further cases will help to a better understanding and clinical characterization of the syndrome.

Clinical and neuroimaging findings in 33 patients with MCAP syndrome: A survey to evaluate relevant endpoints for future clinical trials.

Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient.

FGF14-related episodic ataxia: delineating the phenotype of Episodic Ataxia type 9.

We report four patients from two families who presented attacks of childhood-onset episodic ataxia associated with pathogenic mutations in the FGF14 gene. Attacks were triggered by fever, lasted several days, and had variable frequencies. Nystagmus and/or postural tremor and/or learning disabilities were noticed in individuals harboring FGF14 mutation with or without episodic ataxia. These cases and literature data delineate the FGF14-mutation-related episodic ataxia phenotype: wide range of age at onset (from childhood to adulthood), variable durations and frequencies, triggering factors including fever, and association to chronic symptoms. We propose to add FGF14-related episodic ataxia to the list of primary episodic ataxia as Episodic Ataxia type 9.

Growth charts in Kabuki syndrome 1.

Kabuki syndrome (KS, KS1: OMIM 147920 and KS2: OMIM 300867) is caused by pathogenic variations in KMT2D or KDM6A. KS is characterized by multiple congenital anomalies and neurodevelopmental disorders. Growth restriction is frequently reported. Here we aimed to create specific growth charts for individuals with KS1, identify parameters used for size prognosis and investigate the impact of growth hormone therapy on adult height. Growth parameters and parental size were obtained for 95 KS1 individuals (41 females). Growth charts for height, weight, body mass index (BMI) and occipitofrontal circumference were generated in standard deviation values for the first time in KS1. Statural growth of KS1 individuals was compared to parental target size. According to the charts, height, weight, BMI, and occipitofrontal circumference were lower for KS1 individuals than the normative French population. For males and females, the mean growth of KS1 individuals was -2 and -1.8 SD of their parental target size, respectively. Growth hormone therapy did not increase size beyond the predicted size. This study, from the largest cohort available, proposes growth charts for widespread use in the management of KS1, especially for size prognosis and screening of other diseases responsible for growth impairment beyond a calculated specific target size.

Mosaic complete tetrasomy 21 in a fetus with complete atrioventricular septal defect and minor morphological variations.

BACKGROUND: Tetrasomy 21 is a very rare aneuploidy which could clinically resemble a Down syndrome. It was most often described in its partial form than complete. We report the prenatal, pathological and genetic characteristics of a fetus with mosaic complete tetrasomy 21. This is the second well-documented description of a complete tetrasomy 21 in the literature. METHODS: Prenatal and fetal pathological examinations, cytogenetic and molecular analyses were performed to characterize fetal features with tetrasomy 21. RESULTS: Prenatal ultrasound examination revealed an isolated complete atrioventricular septal defect with normal karyotype on amniotic fluid. After termination of pregnancy, clinical examination of the fetus evoked trisomy 21 or Down syndrome. Chromosomal microarray analysis and FISH on lung tissue showed a mosaicism with four copies of chromosome 21 (tetrasomy 21). CONCLUSION: Our observation and the review of the literature reported the possibility of very weak mosaicism and disease-causing confined tissue-specific mosaicism in fetus or alive patients with chromosome 21 aneuploidy, mainly Down syndrome. In case of clinical diagnosis suggestive of Down syndrome, attention must be paid to the risk of false-negative test due to chromosomal mosaicism (very weak percentage, different tissue distribution). To overcome this risk, it is necessary to privilege the diagnostic techniques without culture step and to increase the number of cells and tissues analyzed, if possible. This study highlights the limits of microarray as the unique diagnostic approach in case of weak mosaic and French cytogenetics guidelines recommend to check anomalies seen in microarray by another technique on the same tissue.

Erratum: Author Correction: A framework to identify contributing genes in patients with Phelan-McDermid syndrome.

[This corrects the article DOI: 10.1038/s41525-017-0035-2.].

New insights into minor splicing-a transcriptomic analysis of cells derived from TALS patients.

Minor intron splicing plays a central role in human embryonic development and survival. Indeed, biallelic mutations in RNU4ATAC, transcribed into the minor spliceosomal U4atac snRNA, are responsible for three rare autosomal recessive multimalformation disorders named Taybi-Linder (TALS/MOPD1), Roifman (RFMN), and Lowry-Wood (LWS) syndromes, which associate numerous overlapping signs of varying severity. Although RNA-seq experiments have been conducted on a few RFMN patient cells, none have been performed in TALS, and more generally no in-depth transcriptomic analysis of the ∼700 human genes containing a minor (U12-type) intron had been published as yet. We thus sequenced RNA from cells derived from five skin, three amniotic fluid, and one blood biosamples obtained from seven unrelated TALS cases and from age- and sex-matched controls. This allowed us to describe for the first time the mRNA expression and splicing profile of genes containing U12-type introns, in the context of a functional minor spliceosome. Concerning RNU4ATAC-mutated patients, we show that as expected, they display distinct U12-type intron splicing profiles compared to controls, but that rather unexpectedly mRNA expression levels are mostly unchanged. Furthermore, although U12-type intron missplicing concerns most of the expressed U12 genes, the level of U12-type intron retention is surprisingly low in fibroblasts and amniocytes, and much more pronounced in blood cells. Interestingly, we found several occurrences of introns that can be spliced using either U2, U12, or a combination of both types of splice site consensus sequences, with a shift towards splicing using preferentially U2 sites in TALS patients' cells compared to controls.

Bardet-Biedl syndrome: Antenatal presentation of forty-five fetuses with biallelic pathogenic variants in known Bardet-Biedl syndrome genes.

Bardet-Biedl syndrome (BBS) is an emblematic ciliopathy associated with retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, hypogonadism and renal dysfunction. Before birth, enlarged/cystic kidneys as well as polydactyly are the hallmark signs of BBS to consider in absence of familial history. However, these findings are not specific to BBS, raising the problem of differential diagnoses and prognosis. Molecular diagnosis during pregnancies remains a timely challenge for this heterogeneous disease (22 known genes). We report here the largest cohort of BBS fetuses to better characterize the antenatal presentation. Prenatal ultrasound (US) and/or autopsy data from 74 fetuses with putative BBS diagnosis were collected out of which molecular diagnosis was established in 51 cases, mainly in BBS genes (45 cases) following the classical gene distribution, but also in other ciliopathy genes (6 cases). Based on this, an updated diagnostic decision tree is proposed. No genotype/phenotype correlation could be established but postaxial polydactyly (82%) and renal cysts (78%) were the most prevalent symptoms. However, autopsy revealed polydactyly that was missed by prenatal US in 55% of the cases. Polydactyly must be carefully looked for in pregnancies with apparently isolated renal anomalies in fetuses.