Publications by authors named "Jean Muller"

83 Publications

A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet-Biedl syndrome.

Clin Genet 2021 Feb 14;99(2):318-324. Epub 2020 Nov 14.

Laboratoire de Génétique Médicale, Institut de génétique médicale d'Alsace IGMA, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg UMRS_1112, Strasbourg, France.

Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinitis pigmentosa, obesity, polydactyly, cognitive impairment and renal failure. Pathogenic variants in 24 genes account for the molecular basis of >80% of cases. Toward saturated discovery of the mutational basis of the disorder, we carefully explored our cohorts and identified a hominid-specific SINE-R/VNTR/Alu type F (SVA-F) insertion in exon 13 of BBS1 in eight families. In six families, the repeat insertion was found in trans with c.1169 T > G, p.Met390Arg and in two families the insertion was found in addition to other recessive BBS loci. Whole genome sequencing, de novo assembly and SNP array analysis were performed to characterize the genomic event. This insertion is extremely rare in the general population (found in 8 alleles of 8 BBS cases but not in >10 800 control individuals from gnomAD-SV) and due to a founder effect. Its 2435 bp sequence contains hallmarks of LINE1 mediated retrotransposition. Functional studies with patient-derived cell lines confirmed that the BBS1 SVA-F is deleterious as evidenced by a significant depletion of both mRNA and protein levels. Such findings highlight the importance of dedicated bioinformatics pipelines to identify all types of variation.
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http://dx.doi.org/10.1111/cge.13878DOI Listing
February 2021

Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy.

Nat Genet 2020 11 12;52(11):1145-1150. Epub 2020 Oct 12.

Center for Human Disease Modeling, Duke University Medical Center, Durham, NC, USA.

The influence of genetic background on driver mutations is well established; however, the mechanisms by which the background interacts with Mendelian loci remain unclear. We performed a systematic secondary-variant burden analysis of two independent cohorts of patients with Bardet-Biedl syndrome (BBS) with known recessive biallelic pathogenic mutations in one of 17 BBS genes for each individual. We observed a significant enrichment of trans-acting rare nonsynonymous secondary variants in patients with BBS compared with either population controls or a cohort of individuals with a non-BBS diagnosis and recessive variants in the same gene set. Strikingly, we found a significant over-representation of secondary alleles in chaperonin-encoding genes-a finding corroborated by the observation of epistatic interactions involving this complex in vivo. These data indicate a complex genetic architecture for BBS that informs the biological properties of disease modules and presents a model for secondary-variant burden analysis in recessive disorders.
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http://dx.doi.org/10.1038/s41588-020-0707-1DOI Listing
November 2020

Atypical Retinal Phenotype in a Patient With Alström Syndrome and Biallelic Novel Pathogenic Variants in , Including a Variation.

Front Genet 2020 21;11:938. Epub 2020 Aug 21.

Laboratoire de Génétique Médicale, Institut de Génétique Médicale d'Alsace, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.

Alström syndrome (ALMS) is a rare autosomal recessive multi-organ syndrome considered to date as a ciliopathy and caused by variations in . Phenotypic variability is well-documented, particularly for the systemic disease manifestations; however, early-onset progressive retinal degeneration affecting both cones and rods (cone-rod type) is universal, leading to blindness by the teenage years. Other features include cardiomyopathy, kidney dysfunction, sensorineural deafness, and childhood obesity associated with hyperinsulinemia and type 2 diabetes mellitus. Here, we present an unusual and delayed retinal dystrophy phenotype associated with ALMS in a 14-year-old female, with affected cone function and surprising complete preservation of rod function on serial electroretinograms (ERGs). High-throughput sequencing of the affected proband revealed compound heterozygosity with two novel nonsense variations in the gene, including one variant of inheritance, an unusual finding in autosomal recessive diseases. To confirm the diagnosis in the context of an unusually mild phenotype and identification of novel variations, we demonstrated the biallelic status of the compound heterozygous variations (c.[286C > T];[1211C > G], p.[(Gln96)];[(Ser404)]). This unique case extends our knowledge of the phenotypic variability and the pathogenic variation spectrum in ALMS patients.
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http://dx.doi.org/10.3389/fgene.2020.00938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472914PMC
August 2020

Reproduction Function in Male Patients With Bardet Biedl Syndrome.

J Clin Endocrinol Metab 2020 12;105(12)

Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France.

Purpose: Bardet-Biedl syndrome (BBS) is a ciliopathy with a wide spectrum of symptoms due to primary cilia dysfunction, including genitourinary developmental anomalies as well as impaired reproduction, particularly in males. Primary cilia are known to be required at the following steps of reproduction function: (i) genitourinary organogenesis, (ii) in fetal firing of hypothalamo-pituitary axe, (iii) sperm flagellum structure, and (iv) first zygotic mitosis conducted by proximal sperm centriole. BBS phenotype is not fully understood.

Methods: This study explored all steps of reproduction in 11 French male patients with identified BBS mutations.

Results: BBS patients frequently presented with genitourinary malformations, such as cryptorchidism (5/11), short scrotum (5/8), and micropenis (5/8), but unexpectedly, with normal testis size (7/8). Ultrasonography highlighted epididymal cysts or agenesis of one seminal vesicle in some cases. Sexual hormones levels were normal in all patients except one. Sperm numeration was normal in 8 out of the 10 obtained samples. Five to 45% of sperm presented a progressive motility. Electron microscopy analysis of spermatozoa did not reveal any homogeneous abnormality. Moreover, a psychological approach pointed to a decreased self-confidence linked to blindness and obesity explaining why so few BBS patients express a child wish.

Conclusions: Primary cilia dysfunction in BBS impacts the embryology of the male genital tract, especially epididymis, penis, and scrotum through an insufficient fetal androgen production. However, in adults, sperm structure does not seem to be impacted. These results should be confirmed in a greater BBS patient cohort, focusing on fertility.
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http://dx.doi.org/10.1210/clinem/dgaa551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538103PMC
December 2020

Proteasome subunit PSMC3 variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress.

EMBO Mol Med 2020 07 5;12(7):e11861. Epub 2020 Jun 5.

Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France.

The ubiquitin-proteasome system degrades ubiquitin-modified proteins to maintain protein homeostasis and to control signalling. Whole-genome sequencing of patients with severe deafness and early-onset cataracts as part of a neurological, sensorial and cutaneous novel syndrome identified a unique deep intronic homozygous variant in the PSMC3 gene, encoding the proteasome ATPase subunit Rpt5, which lead to the transcription of a cryptic exon. The proteasome content and activity in patient's fibroblasts was however unaffected. Nevertheless, patient's cells exhibited impaired protein homeostasis characterized by accumulation of ubiquitinated proteins suggesting severe proteotoxic stress. Indeed, the TCF11/Nrf1 transcriptional pathway allowing proteasome recovery after proteasome inhibition is permanently activated in the patient's fibroblasts. Upon chemical proteasome inhibition, this pathway was however impaired in patient's cells, which were unable to compensate for proteotoxic stress although a higher proteasome content and activity. Zebrafish modelling for knockout in PSMC3 remarkably reproduced the human phenotype with inner ear development anomalies as well as cataracts, suggesting that Rpt5 plays a major role in inner ear, lens and central nervous system development.
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http://dx.doi.org/10.15252/emmm.201911861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338805PMC
July 2020

Potential Impact of Umbilical-Cord-Blood Procalcitonin-Based Algorithm on Antibiotics Exposure in Neonates With Suspected Early-Onset Sepsis.

Front Pediatr 2020 17;8:127. Epub 2020 Apr 17.

Clinical Investigation Center 004, INSERM 1413, Nantes University Hospital, Nantes, France.

The incidence of early-onset neonatal infection has greatly decreased, but a new diagnostic approach is needed to avoid overdiagnosis and overtreatment. The aim of this study was to assess the potential impact of an algorithm incorporating umbilical-cord-blood procalcitonin (PCT) level on neonatal antibiotics prescription rate as compared with current practice. We conducted a prospective study in three maternity wards in France. All term and preterm neonates with the usual risk factors for neonatal group B infection were eligible for umbilical-cord-blood PCT testing. We compared the proportion of neonates who were exposed early to antibiotics (before 6 days of life) to that of neonates for whom antibiotics prescription would be indicated according to the PCT-based algorithm. Among the 3,080 neonates included, 1 neonate presented with certain infection and 38 neonates with probable infection. The global antibiotics prescription rate was 4.6% [95% confidence interval (CI), 4.1-5]. With the PCT-based algorithm, the potential decrease in prescription rate would be 1.8% (95% CI, 1.3-2.3), corresponding to a 39% (95% CI, 37.3-40.7) relative reduction in antibiotics exposure ( < 0.05). These results suggest that the umbilical-cord-blood PCT-based algorithm could significantly help the clinicians in their antibiotic prescription decision to decrease neonatal antibiotics exposure as compared with current practice. If validated in a larger interventional randomized study, this approach could help clinicians stratify the risk of early-onset neonatal infection and initiate early antibiotics treatment in newborns at high risk of infection while limiting the deleterious effects of useless prescriptions in non-infected newborns.
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http://dx.doi.org/10.3389/fped.2020.00127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181674PMC
April 2020

High prevalence of Bardet-Biedl syndrome in La Réunion Island is due to a founder variant in ARL6/BBS3.

Clin Genet 2020 08 22;98(2):166-171. Epub 2020 Jun 22.

Laboratoires de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Bardet-Biedl syndrome (BBS) is a rare ciliopathy with variable retinal dystrophy, polydactyly, renal abnormalities, obesity, cognitive impairment, and hypogonadism. Biallelic pathogenic variants have been identified in 24 genes, leading to BBS in an autosomal recessive inheritance pattern. In this study, we investigated a cohort of 16 families (20 individuals) presenting with typical BBS originating from La Réunion Island using sequencing (Sanger and high-throughput methods) and SNP array. In eight families (12 individuals) we identified the same ARL6/BBS3 variation [c.535G > A, p.(Asp179Asn)]. Bioinformatics and functional analyses revealed an effect of this variant on the splicing of ARL6/BBS3. Owing to the relatively high frequency of this variant, a possible founder effect was suspected. Genotyping of six individuals revealed a common 3.8-Mb haplotype and estimated the most recent common ancestor to about eight generations confirmed by the known genealogy. Knowledge of this founder effect modifies our diagnostic strategy and enables a personalized genetic counseling for patients from La Réunion Island. Being the first description of BBS patients from La Réunion Island, we could estimate its prevalence between ~1/45000 and ~ 1/66000 individuals.
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http://dx.doi.org/10.1111/cge.13768DOI Listing
August 2020

Homozygous Splice Site Mutation in Causes Familial Oocyte Maturation Defect.

Genes (Basel) 2020 04 1;11(4). Epub 2020 Apr 1.

Institut de Parasitologie et Pathologie Tropicale, EA 7292, Fédération de Médecine Translationelle (IPPTS), Université de Strasbourg, 3 rue Koeberlé, 67000 Strasbourg, France.

In vitro fertilization (IVF) involves controlled ovarian hyperstimulation using hormones to produce large numbers of oocytes. The success of IVF is tightly linked to the availability of mature oocytes. In most cases, about 70% to 80% of the oocytes are mature at the time of retrieval, however, in rare instances, all of them may be immature, implying that they were not able to reach the metaphase II (MII) stage. The failure to obtain any mature oocytes, despite a well conducted ovarian stimulation in repeated cycles is a very rare cause of primary female infertility, for which the underlying suspected genetic factors are still largely unknown. In this study, we present the whole exome sequencing analysis of a consanguineous Turkish family comprising three sisters with a recurrent oocyte maturation defect. Analysis of the data reveals a homozygous splice site mutation (c.1775-3C>A) in the zona pellucida glycoprotein 1 () gene. Minigene experiments show that the mutation causes the retention of the intron 11 sequence between exon 11 and exon 12, resulting in a frameshift and the likely production of a truncated protein.
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http://dx.doi.org/10.3390/genes11040382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231235PMC
April 2020

Novel IQCE variations confirm its role in postaxial polydactyly and cause ciliary defect phenotype in zebrafish.

Hum Mutat 2020 01 17;41(1):240-254. Epub 2019 Oct 17.

Laboratoire de Génétique médicale, UMR_S INSERM U1112, IGMA, Faculté de Médecine, FMTS, Université de Strasbourg, Strasbourg, France.

Polydactyly is one of the most frequent inherited defects of the limbs characterized by supernumerary digits and high-genetic heterogeneity. Among the many genes involved, either in isolated or syndromic forms, eight have been implicated in postaxial polydactyly (PAP). Among those, IQCE has been recently identified in a single consanguineous family. Using whole-exome sequencing in patients with uncharacterized ciliopathies, including PAP, we identified three families with biallelic pathogenic variations in IQCE. Interestingly, the c.895_904del (p.Val301Serfs*8) was found in all families without sharing a common haplotype, suggesting a recurrent mechanism. Moreover, in two families, the systemic phenotype could be explained by additional pathogenic variants in known genes (TULP1, ATP6V1B1). RNA expression analysis on patients' fibroblasts confirms that the dysfunction of IQCE leads to the dysregulation of genes associated with the hedgehog-signaling pathway, and zebrafish experiments demonstrate a full spectrum of phenotypes linked to defective cilia: Body curvature, kidney cysts, left-right asymmetry, misdirected cilia in the pronephric duct, and retinal defects. In conclusion, we identified three additional families confirming IQCE as a nonsyndromic PAP gene. Our data emphasize the importance of taking into account the complete set of variations of each individual, as each clinical presentation could finally be explained by multiple genes.
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http://dx.doi.org/10.1002/humu.23924DOI Listing
January 2020

Rare De Novo Missense Variants in RNA Helicase DDX6 Cause Intellectual Disability and Dysmorphic Features and Lead to P-Body Defects and RNA Dysregulation.

Am J Hum Genet 2019 09 15;105(3):509-525. Epub 2019 Aug 15.

Institute of Genetics and Molecular and Cellular Biology, Illkirch, France; French National Center for Scientific Research, UMR7104, 67400 Illkirch, France; National Institute of Health and Medical Research U964, 67400 Illkirch, France; University of Strasbourg, 67081 Illkirch, France; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address:

The human RNA helicase DDX6 is an essential component of membrane-less organelles called processing bodies (PBs). PBs are involved in mRNA metabolic processes including translational repression via coordinated storage of mRNAs. Previous studies in human cell lines have implicated altered DDX6 in molecular and cellular dysfunction, but clinical consequences and pathogenesis in humans have yet to be described. Here, we report the identification of five rare de novo missense variants in DDX6 in probands presenting with intellectual disability, developmental delay, and similar dysmorphic features including telecanthus, epicanthus, arched eyebrows, and low-set ears. All five missense variants (p.His372Arg, p.Arg373Gln, p.Cys390Arg, p.Thr391Ile, and p.Thr391Pro) are located in two conserved motifs of the RecA-2 domain of DDX6 involved in RNA binding, helicase activity, and protein-partner binding. We use functional studies to demonstrate that the first variants identified (p.Arg373Gln and p.Cys390Arg) cause significant defects in PB assembly in primary fibroblast and model human cell lines. These variants' interactions with several protein partners were also disrupted in immunoprecipitation assays. Further investigation via complementation assays included the additional variants p.Thr391Ile and p.Thr391Pro, both of which, similarly to p.Arg373Gln and p.Cys390Arg, demonstrated significant defects in P-body assembly. Complementing these molecular findings, modeling of the variants on solved protein structures showed distinct spatial clustering near known protein binding regions. Collectively, our clinical and molecular data describe a neurodevelopmental syndrome associated with pathogenic missense variants in DDX6. Additionally, we suggest DDX6 join the DExD/H-box genes DDX3X and DHX30 in an emerging class of neurodevelopmental disorders involving RNA helicases.
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http://dx.doi.org/10.1016/j.ajhg.2019.07.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731366PMC
September 2019

The Molecular Architecture of Native BBSome Obtained by an Integrated Structural Approach.

Structure 2019 09 11;27(9):1384-1394.e4. Epub 2019 Jul 11.

Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Molecular Electron Microscopy, The Rockefeller University, New York, NY 10065, USA. Electronic address:

The unique membrane composition of cilia is maintained by a diffusion barrier at the transition zone that is breached when the BBSome escorts signaling receptors out of cilia. Understanding how the BBSome removes proteins from cilia has been hampered by a lack of structural information. Here, we present a nearly complete Cα model of BBSome purified from cow retina. The model is based on a single-particle cryo-electron microscopy density map at 4.9-Å resolution that was interpreted with the help of comprehensive Rosetta-based structural modeling constrained by crosslinking mass spectrometry data. We find that BBSome subunits have a very high degree of interconnectivity, explaining the obligate nature of the complex. Furthermore, like other coat adaptors, the BBSome exists in an autoinhibited state in solution and must thus undergo a conformational change upon recruitment to membranes by the small GTPase ARL6/BBS3. Our model provides the first detailed view of the machinery enabling ciliary exit.
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http://dx.doi.org/10.1016/j.str.2019.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726506PMC
September 2019

Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy.

Hum Mutat 2019 10 18;40(10):1826-1840. Epub 2019 Jun 18.

Laboratoire de Génétique Médicale, INSERM U1112, Institut de Génétique Médicale d'Alsace, Université de Strasbourg, Strasbourg, France.

Mutations in genes encoding aminoacyl-tRNA synthetases have been reported in several neurological disorders. KARS is a dual localized lysyl-tRNA synthetase and its cytosolic isoform belongs to the multiple aminoacyl-tRNA synthetase complex (MSC). Biallelic mutations in the KARS gene were described in a wide phenotypic spectrum ranging from nonsyndromic deafness to complex impairments. Here, we report on a patient with severe neurological and neurosensory disease investigated by whole-exome sequencing and found to carry biallelic mutations c.683C>T (p.Pro228Leu) and c.871T>G (p.Phe291Val), the second one being novel, in the KARS gene. The patient presented with an atypical clinical presentation with an optic neuropathy not previously reported. At the cellular level, we show that cytoplasmic KARS was expressed at a lower level in patient cells and displayed decreased interaction with MSC. In vitro, these two KARS variants have a decreased aminoacylation activity compared with wild-type KARS, the p.Pro228Leu being the most affected. Our data suggest that dysfunction of cytoplasmic KARS resulted in a decreased level of translation of the nuclear-encoded lysine-rich proteins belonging to the respiratory chain complex, thus impairing mitochondria functions.
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http://dx.doi.org/10.1002/humu.23799DOI Listing
October 2019

Protocol GenoDENT: Implementation of a New NGS Panel for Molecular Diagnosis of Genetic Disorders with Orodental Involvement.

Methods Mol Biol 2019 ;1922:407-452

Faculté de Chirurgie Dentaire, Université de Strasbourg, Strasbourg, France.

Rare genetic disorders are often challenging to diagnose. Anomalies of tooth number, shape, size, mineralized tissue structure, eruption, and resorption may exist as isolated symptoms or diseases but are often part of the clinical synopsis of numerous syndromes (Bloch-Zupan A, Sedano H, Scully C. Dento/oro/craniofacial anomalies and genetics, 1st edn. Elsevier, Boston, MA, 2012). Concerning amelogenesis imperfecta (AI), for example, mutations in a number of genes have been reported to cause isolated AI, including AMELX, ENAM, KLK4, MMP20, FAM83H, WDR72, C4orf26, SLC24A4, and LAMB3. In addition, many other genes such as DLX3, CNNM4, ROGDI, FAM20A, STIM1, ORAI1, and LTBP3 have been shown to be involved in developmental syndromes with enamel defects. The clinical presentation of the enamel phenotype (hypoplastic, hypomineralized, hypomature, or a combination of severities) alone does not allow a reliable prediction of possible causative genetic mutations. Understanding the potential genetic cause(s) of rare diseases is critical for overall health management of affected patient. One effective strategy to reach a genetic diagnosis is to sequence a selected gene panel chosen for a determined range of phenotypes. Here we describe a laboratory protocol to set up a specific gene panel for orodental diseases.
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http://dx.doi.org/10.1007/978-1-4939-9012-2_36DOI Listing
June 2019

Identification and Characterization of Known Biallelic Mutations in the () Gene in a Novel Family With Bardet-Biedl Syndrome.

Front Genet 2019 30;10:21. Epub 2019 Jan 30.

Laboratoire de Génétique Médicale, Institut de Génétique Médicale d'Alsace, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France.

Bardet-Biedl syndrome (BBS; MIM 209900) is a rare ciliopathy characterized by retinitis pigmentosa, postaxial polydactyly, obesity, hypogonadism, cognitive impairment and kidney dysfunction. Mutations in 22 BBS genes have been identified to cause the disease. We report a family with typical BBS features (retinitis pigmentosa, postaxial polydactyly, obesity, cognitive impairment, and atrioventricular septal defect) mutated in . IFT27 is part of the Intraflagellar transport (IFT), a bidirectional mechanism allowing the protein motility within the cilia. Using whole exome sequencing, two compound heterozygous mutations were found in the proband (NM_006860.4:c.[104A > G];[349+1G > T], p.[Tyr35Cys];[?]) consistent with the expected autosomal recessive inheritance mode. These two mutations have already been reported but independently in other families and lacking either familial segregation or functional validation. This is the third report of mutations in BBS patients confirming as a BBS gene (). Mutations in IFT genes ( and ) confirm the IFT-pathway as a pathomechanism for BBS.
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http://dx.doi.org/10.3389/fgene.2019.00021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363664PMC
January 2019

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

Clin Genet 2019 03;95(3):384-397

Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

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.
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http://dx.doi.org/10.1111/cge.13500DOI Listing
March 2019

Genetic Evidence Supporting the Role of the Calcium Channel, CACNA1S, in Tooth Cusp and Root Patterning.

Front Physiol 2018 26;9:1329. Epub 2018 Sep 26.

Biofilm Research Group, Department of Pediatric Dentistry, Faculty of Dentistry, Khon Kaen University, Khon Kaen, Thailand.

In this study, we report a unique dominantly inherited disorganized supernumerary cusp and single root phenotype presented by 11 affected individuals belonging to 5 north-eastern Thai families. Using whole exome sequencing (WES) we identified a common single missense mutation that segregates with the phenotype in exon 6 of (Ca1.1) (NM_000069.2: c.[865A > G];[=] p.[Ile289Val];[=]), the Calcium Channel, Voltage-Dependent, L Type, Alpha-1s Subunit, OMIM 114208), affecting a highly conserved amino-acid isoleucine residue within the pore forming subdomain of CACNA1S protein. This is a strong genetic evidence that a voltage-dependent calcium ion channel is likely to play a role in influencing tooth morphogenesis and patterning.
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http://dx.doi.org/10.3389/fphys.2018.01329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170876PMC
September 2018

Genetic evaluation of patients with non-syndromic male infertility.

J Assist Reprod Genet 2018 Nov 26;35(11):1939-1951. Epub 2018 Sep 26.

Institut de Parasitologie et Pathologie Tropicale, EA 7292, Fédération de Médecine Translationelle (IPPTS), Université de Strasbourg, 3 rue Koeberlé, 67000, Strasbourg, France.

Purpose: This review provides an update on the genetics of male infertility with emphasis on the current state of research, the genetic disorders that can lead to non-syndromic male infertility, and the genetic tests available for patients.

Methods: A comprehensive review of the scientific literature referenced in PubMed was conducted using keywords related to male infertility and genetics. The search included articles with English abstracts appearing online after 2000.

Results: Mutations in 31 distinct genes have been identified as a cause of non-syndromic human male infertility, and the number is increasing constantly. Screening gene panels by high-throughput sequencing can be offered to patients in order to identify genes involved in various forms of human non-syndromic infertility. We propose a workflow for genetic tests which takes into account semen alterations.

Conclusions: The identification and characterization of the genetic basis of male infertility have broad implications not only for understanding the cause of infertility but also in determining the prognosis, selection of treatment options, and management of couples. Genetic diagnosis is essential for the success of ART techniques and for preserving future fertility as well as the prognosis for testicular sperm extraction (TESE) and adopted therapeutics.
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http://dx.doi.org/10.1007/s10815-018-1301-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240550PMC
November 2018

CoDE-seq, an augmented whole-exome sequencing, enables the accurate detection of CNVs and mutations in Mendelian obesity and intellectual disability.

Mol Metab 2018 07 16;13:1-9. Epub 2018 May 16.

CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, France; Department of Medicine, Section of Genomics of Common Disease, Imperial College London, London, United Kingdom. Electronic address:

Objective: The molecular diagnosis of extreme forms of obesity, in which accurate detection of both copy number variations (CNVs) and point mutations, is crucial for an optimal care of the patients and genetic counseling for their families. Whole-exome sequencing (WES) has benefited considerably this molecular diagnosis, but its poor ability to detect CNVs remains a major limitation. We aimed to develop a method (CoDE-seq) enabling the accurate detection of both CNVs and point mutations in one step.

Methods: CoDE-seq is based on an augmented WES method, using probes distributed uniformly throughout the genome. CoDE-seq was validated in 40 patients for whom chromosomal DNA microarray was available. CNVs and mutations were assessed in 82 children/young adults with suspected Mendelian obesity and/or intellectual disability and in their parents when available (n = 145).

Results: CoDE-seq not only detected all of the 97 CNVs identified by chromosomal DNA microarrays but also found 84 additional CNVs, due to a better resolution. When compared to CoDE-seq and chromosomal DNA microarrays, WES failed to detect 37% and 14% of CNVs, respectively. In the 82 patients, a likely molecular diagnosis was achieved in >30% of the patients. Half of the genetic diagnoses were explained by CNVs while the other half by mutations.

Conclusions: CoDE-seq has proven cost-efficient and highly effective as it avoids the sequential genetic screening approaches currently used in clinical practice for the accurate detection of CNVs and point mutations.
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http://dx.doi.org/10.1016/j.molmet.2018.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026315PMC
July 2018

Whole-genome sequencing in patients with ciliopathies uncovers a novel recurrent tandem duplication in IFT140.

Hum Mutat 2018 07 8;39(7):983-992. Epub 2018 May 8.

Laboratoire de Génétique médicale, UMR_S INSERM U1112, IGMA, Faculté de Médecine FMTS, Université de Strasbourg, Strasbourg, France.

Ciliopathies represent a wide spectrum of rare diseases with overlapping phenotypes and a high genetic heterogeneity. Among those, IFT140 is implicated in a variety of phenotypes ranging from isolated retinis pigmentosa to more syndromic cases. Using whole-genome sequencing in patients with uncharacterized ciliopathies, we identified a novel recurrent tandem duplication of exon 27-30 (6.7 kb) in IFT140, c.3454-488_4182+2588dup p.(Tyr1152_Thr1394dup), missed by whole-exome sequencing. Pathogenicity of the mutation was assessed on the patients' skin fibroblasts. Several hundreds of patients with a ciliopathy phenotype were screened and biallelic mutations were identified in 11 families representing 12 pathogenic variants of which seven are novel. Among those unrelated families especially with a Mainzer-Saldino syndrome, eight carried the same tandem duplication (two at the homozygous state and six at the heterozygous state). In conclusion, we demonstrated the implication of structural variations in IFT140-related diseases expanding its mutation spectrum. We also provide evidences for a unique genomic event mediated by an Alu-Alu recombination occurring on a shared haplotype. We confirm that whole-genome sequencing can be instrumental in the ability to detect structural variants for genomic disorders.
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http://dx.doi.org/10.1002/humu.23539DOI Listing
July 2018

AnnotSV: an integrated tool for structural variations annotation.

Bioinformatics 2018 10;34(20):3572-3574

Laboratoire de Génétique Médicale, UMR_S INSERM U1112, IGMA, Faculté de Médecine FMTS, Université de Strasbourg, Strasbourg, France.

Summary: Structural Variations (SV) are a major source of variability in the human genome that shaped its actual structure during evolution. Moreover, many human diseases are caused by SV, highlighting the need to accurately detect those genomic events but also to annotate them and assist their biological interpretation. Therefore, we developed AnnotSV that compiles functionally, regulatory and clinically relevant information and aims at providing annotations useful to (i) interpret SV potential pathogenicity and (ii) filter out SV potential false positive. In particular, AnnotSV reports heterozygous and homozygous counts of single nucleotide variations (SNVs) and small insertions/deletions called within each SV for the analyzed patients, this genomic information being extremely useful to support or question the existence of an SV. We also report the computed allelic frequency relative to overlapping variants from DGV (MacDonald et al., 2014), that is especially powerful to filter out common SV. To delineate the strength of AnnotSV, we annotated the 4751 SV from one sample of the 1000 Genomes Project, integrating the sample information of four million of SNV/indel, in less than 60 s.

Availability And Implementation: AnnotSV is implemented in Tcl and runs in command line on all platforms. The source code is available under the GNU GPL license. Source code, README and Supplementary data are available at http://lbgi.fr/AnnotSV/.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/bty304DOI Listing
October 2018

PLCB3 Loss of Function Reduces Pseudomonas aeruginosa-Dependent IL-8 Release in Cystic Fibrosis.

Am J Respir Cell Mol Biol 2018 10;59(4):428-436

2 Laboratory of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, Verona, Italy.

The lungs of patients with cystic fibrosis (CF) are characterized by an exaggerated inflammation driven by secretion of IL-8 from bronchial epithelial cells and worsened by Pseudomonas aeruginosa infection. To identify novel antiinflammatory molecular targets, we previously performed a genetic study of 135 genes of the immune response, which identified the c.2534C>T (p.S845L) variant of phospholipase C-β3 (PLCB3) as being significantly associated with mild progression of pulmonary disease. Silencing PLCB3 revealed that it potentiates the Toll-like receptor's inflammatory signaling cascade originating from CF bronchial epithelial cells. In the present study, we investigated the role of the PLCB3-S845L variant together with two synthetic mutants paradigmatic of impaired catalytic activity or lacking functional activation in CF bronchial epithelial cells. In experiments in which cells were exposed to P. aeruginosa, the supernatant of mucopurulent material from the airways of patients with CF or different agonists revealed that PLCB3-S845L has defects of 1) agonist-induced Ca release from endoplasmic reticulum and rise of Ca concentration, 2) activation of conventional protein kinase C isoform β, and 3) induction of IL-8 release. These results, besides identifying S845L as a loss-of-function variant, strengthen the importance of targeting PLCB3 to mitigate the CF inflammatory response in bronchial epithelial cells without blunting the immune response.
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http://dx.doi.org/10.1165/rcmb.2017-0267OCDOI Listing
October 2018

Mesenchymal stromal cells' role in tumor microenvironment: involvement of signaling pathways.

Cancer Biol Med 2017 May;14(2):129-141

Department of Biomedical Sciences, University of Ngaoundere, Ngaoundere 454, Cameroon.

Mesenchymal stromal cells (MSCs) are adult multipotent stem cells residing as pericytes in various tissues and organs where they can differentiate into specialized cells to replace dying cells and damaged tissues. These cells are commonly found at injury sites and in tumors that are known to behave like " wounds that do not heal." In this article, we discuss the mechanisms of MSCs in migrating, homing, and repairing injured tissues. We also review a number of reports showing that tumor microenvironment triggers plasticity mechanisms in MSCs to induce malignant neoplastic tissue formation, maintenance, and chemoresistance, as well as tumor growth. The antitumor properties and therapeutic potential of MSCs are also discussed.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2016.0033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444925PMC
May 2017

Developmental pathways associated with cancer metastasis: Notch, Wnt, and Hedgehog.

Cancer Biol Med 2017 May;14(2):109-120

Department of Biomedical Sciences, University of Ngaoundere, Ngaoundere 454, Cameroon.

Master developmental pathways, such as Notch, Wnt, and Hedgehog, are signaling systems that control proliferation, cell death, motility, migration, and stemness. These systems are not only commonly activated in many solid tumors, where they drive or contribute to cancer initiation, but also in primary and metastatic tumor development. The reactivation of developmental pathways in cancer stroma favors the development of cancer stem cells and allows their maintenance, indicating these signaling pathways as particularly attractive targets for efficient anticancer therapies, especially in advanced primary tumors and metastatic cancers. Metastasis is the worst feature of cancer development. This feature results from a cascade of events emerging from the hijacking of epithelial-mesenchymal transition, angiogenesis, migration, and invasion by transforming cells and is associated with poor survival, drug resistance, and tumor relapse. In the present review, we summarize and discuss experimental data suggesting pivotal roles for developmental pathways in cancer development and metastasis, considering the therapeutic potential. Emerging targeted antimetastatic therapies based on Notch, Wnt, and Hedgehog pathways are also discussed.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2016.0032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444923PMC
May 2017

A no-stop mutation in MAGEB4 is a possible cause of rare X-linked azoospermia and oligozoospermia in a consanguineous Turkish family.

J Assist Reprod Genet 2017 May 11;34(5):683-694. Epub 2017 Apr 11.

Département Génomique Fonctionnelle et Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de Santé et de Recherche Médicale (INSERM) U964/Centre National de Recherche Scientifique (CNRS) UMR 7104, Université de Strasbourg, 67404, Illkirch, France.

Purpose: The purpose of this study was to identify mutations that cause non-syndromic male infertility using whole exome sequencing of family cases.

Methods: We recruited a consanguineous Turkish family comprising nine siblings with male triplets; two of the triplets were infertile as well as one younger infertile brother. Whole exome sequencing (WES) performed on two azoospermic brothers identified a mutation in the melanoma antigen family B4 (MAGEB4) gene which was confirmed via Sanger sequencing and then screened for on control groups and unrelated infertile subjects. The effect of the mutation on messenger RNA (mRNA) and protein levels was tested after in vitro cell transfection. Structural features of MAGEB4 were predicted throughout the conserved MAGE domain.

Results: The novel single-base substitution (c.1041A>T) in the X-linked MAGEB4 gene was identified as a no-stop mutation. The mutation is predicted to add 24 amino acids to the C-terminus of MAGEB4. Our functional studies were unable to detect any effect either on mRNA stability, intracellular localization of the protein, or the ability to homodimerize/heterodimerize with other MAGE proteins. We thus hypothesize that these additional amino acids may affect the proper protein interactions with MAGEB4 partners.

Conclusion: The whole exome analysis of a consanguineous Turkish family revealed MAGEB4 as a possible new X-linked cause of inherited male infertility. This study provides the first clue to the physiological function of a MAGE protein.
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http://dx.doi.org/10.1007/s10815-017-0900-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427651PMC
May 2017

SCA13 causes dominantly inherited non-progressive myoclonus ataxia.

Parkinsonism Relat Disord 2017 05 11;38:80-84. Epub 2017 Feb 11.

Département de Neurologie, Hôpital de Hautepierre, CHU de Strasbourg, Strasbourg, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Illkirch, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France. Electronic address:

Introduction: Spinocerebellar ataxia 13 (SCA13) is a rare autosomal dominant cerebellar ataxia. To our knowledge, its association to movement disorders has never been described. We aimed at reporting 8 new SCA13 cases with a focus on movement disorders especially myoclonus.

Methods: We performed a detailed neurological examination and neurophysiological recording in 8 patients consecutively diagnosed with SCA13 between December 2013 and October 2015 and followed up in two French tertiary centers.

Results: We identified mild subcortical myoclonus in all patients, with a homogenous clinical and electrophysiological pattern. Myoclonus ataxia was very slowly progressive, like the other symptoms of the disease, whatever the age of onset. Patients with R423H mutation had an earlier age of onset than patients with R420H mutation.

Conclusions: Myoclonus appears to be frequent in SCA13. SCA13 should be considered facing non-progressive autosomal dominant myoclonus ataxia, and polymyographic recording should be included in the diagnosis work.
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http://dx.doi.org/10.1016/j.parkreldis.2017.02.012DOI Listing
May 2017

Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome.

Eur J Hum Genet 2017 04 8;25(4):423-431. Epub 2017 Feb 8.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.

Fragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat sequence in the 5'-UTR of the FMR1 gene, therefore, routinely tested in ID patients. We report here three FMR1 intragenic pathogenic variants not affecting this sequence, identified using high-throughput sequencing (HTS): a previously reported hemizygous deletion encompassing the last exon of FMR1, too small to be detected by array-CGH and inducing decreased expression of a truncated form of FMRP protein, in three brothers with ID (family 1) and two splice variants in boys with sporadic ID: a de novo variant c.990+1G>A (family 2) and a maternally inherited c.420-8A>G variant (family 3). After clinical reevaluation, the five patients presented features consistent with FXS (mean Hagerman's scores=15). We conducted a systematic review of all rare non-synonymous variants previously reported in FMR1 in ID patients and showed that six of them are convincing pathogenic variants. This study suggests that intragenic FMR1 variants, although much less frequent than CGG expansions, are a significant mutational mechanism leading to FXS and demonstrates the interest of HTS approaches to detect them in ID patients with a negative standard work-up.
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http://dx.doi.org/10.1038/ejhg.2016.204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386424PMC
April 2017

Expanding the spectrum of PEX10-related peroxisomal biogenesis disorders: slowly progressive recessive ataxia.

J Neurol 2016 Aug 26;263(8):1552-8. Epub 2016 May 26.

Laboratoire de Génétique de Maladies Rares, Institut Universitaire de Recherche Clinique, EA7402, Université de Montpellier, CHU Montpellier, 641 Avenue du Doyen Gaston Giraud, 34093, Montpellier Cedex 5, France.

Peroxisomal biogenesis disorders (PBDs) consist of a heterogeneous group of autosomal recessive diseases, in which peroxisome assembly and proliferation are impaired leading to severe multisystem disease and early death. PBDs include Zellweger spectrum disorders (ZSDs) with a relatively mild clinical phenotype caused by PEX1, (MIM# 602136), PEX2 (MIM# 170993), PEX6 (MIM# 601498), PEX10 (MIM# 602859), PEX12 (MIM# 601758), and PEX16 (MIM# 603360) mutations. Three adult patients are reported belonging to a non-consanguineous French family affected with slowly progressive cerebellar ataxia, axonal neuropathy, and pyramidal signs. Mental retardation and diabetes mellitus were optional. The age at onset was in childhood or in adolescence (3-15 years). Brain MRI showed marked cerebellar atrophy. Biochemical blood analyses suggested a mild peroxisomal defect. With whole exome sequencing, two mutations in PEX10 were found in the three patients: c.827G>T (novel) causing the missense change p.Cys276Phe and c.932G>A causing the missense change p.Arg311Gln. The phenotypic spectrum related to PEX10 mutations includes slowly progressive, syndromic recessive ataxia.
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http://dx.doi.org/10.1007/s00415-016-8167-3DOI Listing
August 2016

Validation of a clinical practice-based algorithm for the diagnosis of autosomal recessive cerebellar ataxias based on NGS identified cases.

J Neurol 2016 Jul 3;263(7):1314-22. Epub 2016 May 3.

Laboratoire de Génétique de Maladies Rares, Institut Universitaire de Recherche Clinique, Université de Montpellier, EA 7402, CHU Montpellier, 34093, Montpellier, France.

Establishing a molecular diagnosis of autosomal recessive cerebellar ataxias (ARCA) is challenging due to phenotype and genotype heterogeneity. We report the validation of a previously published clinical practice-based algorithm to diagnose ARCA. Two assessors performed a blind analysis to determine the most probable mutated gene based on comprehensive clinical and paraclinical data, without knowing the molecular diagnosis of 23 patients diagnosed by targeted capture of 57 ataxia genes and high-throughput sequencing coming from a 145 patients series. The correct gene was predicted in 61 and 78 % of the cases by the two assessors, respectively. There was a high inter-rater agreement [K = 0.85 (0.55-0.98) p < 0.001] confirming the algorithm's reproducibility. Phenotyping patients with proper clinical examination, imaging, biochemical investigations and nerve conduction studies remain crucial for the guidance of molecular analysis and to interpret next generation sequencing results. The proposed algorithm should be helpful for diagnosing ARCA in clinical practice.
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http://dx.doi.org/10.1007/s00415-016-8112-5DOI Listing
July 2016

Uncommon nucleotide excision repair phenotypes revealed by targeted high-throughput sequencing.

Orphanet J Rare Dis 2016 Mar 22;11:26. Epub 2016 Mar 22.

Laboratoire de Génétique Médicale - INSERM U1112, Institut de Génétique Médicale d'Alsace (IGMA), Faculté de médecine de Strasbourg, 11 rue Humann, Strasbourg, France.

Background: Deficient nucleotide excision repair (NER) activity causes a variety of autosomal recessive diseases including xeroderma pigmentosum (XP) a disorder which pre-disposes to skin cancer, and the severe multisystem condition known as Cockayne syndrome (CS). In view of the clinical overlap between NER-related disorders, as well as the existence of multiple phenotypes and the numerous genes involved, we developed a new diagnostic approach based on the enrichment of 16 NER-related genes by multiplex amplification coupled with next-generation sequencing (NGS).

Methods: Our test cohort consisted of 11 DNA samples, all with known mutations and/or non pathogenic SNPs in two of the tested genes. We then used the same technique to analyse samples from a prospective cohort of 40 patients. Multiplex amplification and sequencing were performed using AmpliSeq protocol on the Ion Torrent PGM (Life Technologies).

Results: We identified causative mutations in 17 out of the 40 patients (43%). Four patients showed biallelic mutations in the ERCC6(CSB) gene, five in the ERCC8(CSA) gene: most of them had classical CS features but some had very mild and incomplete phenotypes. A small cohort of 4 unrelated classic XP patients from the Basque country (Northern Spain) revealed a common splicing mutation in POLH (XP-variant), demonstrating a new founder effect in this population. Interestingly, our results also found ERCC2(XPD), ERCC3(XPB) or ERCC5(XPG) mutations in two cases of UV-sensitive syndrome and in two cases with mixed XP/CS phenotypes.

Conclusions: Our study confirms that NGS is an efficient technique for the analysis of NER-related disorders on a molecular level. It is particularly useful for phenotypes with combined features or unusually mild symptoms. Targeted NGS used in conjunction with DNA repair functional tests and precise clinical evaluation permits rapid and cost-effective diagnosis in patients with NER-defects.
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http://dx.doi.org/10.1186/s13023-016-0408-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804614PMC
March 2016

Identification of a novel mutation confirms the implication of IFT172 (BBS20) in Bardet-Biedl syndrome.

J Hum Genet 2016 May 14;61(5):447-50. Epub 2016 Jan 14.

Laboratoire de Génétique Médicale, Institut de Génétique Médicale d'Alsace, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.

Bardet-Biedl syndrome (BBS; MIM 209900) is a recessive heterogeneous ciliopathy characterized by retinitis pigmentosa (RP), postaxial polydactyly, obesity, hypogonadism, cognitive impairment and kidney dysfunction. So far, 20 BBS genes have been identified, with the last reported ones being found in one or very few families. Whole-exome sequencing was performed in a consanguineous family in which two affected children presented typical BBS features (retinitis pigmentosa, postaxial polydactyly, obesity, hypogonadism and cognitive impairment) without any mutation identified in known BBS genes at the time of the study. We identified a homozygous splice-site mutation (NM_015662.2: c.4428+3A>G) in both affected siblings in the last reported BBS gene, namely, Intraflagellar Transport 172 Homolog (IFT172). Familial mutation segregation was consistent with autosomal recessive inheritance. IFT172 mutations were initially reported in Jeune and Mainzer-Saldino syndromes. Recently, mutations have also been found in isolated RP and Bardet-Biedl-like ciliopathy. This is the second report of IFT172 mutations in BBS patients validating IFT172 as the twentieth BBS gene (BBS20). Moreover, another IFT gene, IFT27, was already associated with BBS, confirming the implication of IFT genes in the pathogenesis of BBS.
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http://dx.doi.org/10.1038/jhg.2015.162DOI Listing
May 2016