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Saadullah Khan - One of the best experts on this subject based on the ideXlab platform.
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association of sequence variants in frizzled 6 with autosomal recessive Nail Dysplasia ndnc 10 in pashtun families
Journal of Pakistan Medical Association, 2019Co-Authors: Saadullah Khan, Anwar Kamal Khan, Malaika Hamid, Muhammad Nazif, Muhammad Azeem Abbas, Sher Alam Khan, Bushra Khan, M A Khan, Abid Jan, Baharullah KhattakAbstract:Primitive epidermis develops the Nail apparatus. Nails have a strong and inflexible Nail plate at the end of each digit. Very few genes responsible for causing nonsyndromic form of Nail Dysplasia have been reported. In the current study, peripheral blood samples were collectedfrom three unaffected individuals and four affectedindividuals of Family A, while blood from two affected and three unaffected individuals were taken of Family B. Genotyping in both the families was performed using highly polymorphic short tandem repeat microsatellite markers. Sanger sequence of the FZD6 gene was performed and analysed for segregation analysis. A comparative modelling approach was used to predict the three-dimensional structures of FZD-6 protein using Modeller 4. Linkage analysis mapped a disease locus on chromosome 8q22.3, harbouring FZD6. Targeted Sanger sequencing of all the coding exons of FZD6 revealed a nonsense sequence variant in pedigree A, whereas a missense sequence variant in pedigree B. Finding and literature indicates the disease spectrum of Pakistani population with claw-shaped Nail Dysplasia, particularly in families of Pashtun origin.
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A novel mutation in homeobox DNA binding domain of HOXC13 gene underlies pure hair and Nail ectodermal Dysplasia (ECTD9) in a Pakistani family
BMC Medical Genetics, 2017Co-Authors: Anwar Kamal Khan, Sher Alam Khan, Noor Muhammad, Abdul Aziz, Khadim Shah, Abdul Nasir, Muzammil Ahmad Khan, Saadullah KhanAbstract:Background Pure hair and Nail ectodermal Dysplasia (PHNED) is a congenital disorder of hair abnormalities and Nail Dysplasia. Both autosomal recessive and dominant inheritance fashion of PHNED occurs. In literature, to date, five different forms of PHNED have been reported at molecular level, having three genes known and two loci with no gene yet. Methods In this study, a four generations consanguineous family of Pakistani origin with autosomal recessive PHNED was investigated. Affected members exhibited PHNED phenotypes with involvement of complete hair loss and Nail Dysplasia. To screen for mutation in the genes ( HOXC13 , KRT74 , KRT85 ), its coding exons and exons-intron boundaries were sequenced. The 3D models of normal and mutated HOXC13 were predicted by using homology modeling. Results Through investigating the family to known loci, the family was mapped to ectodermal Dysplasia 9 (ECTD9) loci with genetic address of 12q13.13. Mutation screening revealed a novel missense mutation (c.929A > C; p.Asn310Thr) in homeobox DNA binding domain of HOXC13 gene in affected members of the family. Due to mutation, loss of hydrogen bonding and difference in potential energy occurs, which may resulting in alteration of protein function. Conclusion This is the first mutation reported in homeodomain, while 5^th mutation reported in HOXC13 gene causing PHNED.
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a novel mutation in homeobox dna binding domain of hoxc13 gene underlies pure hair and Nail ectodermal Dysplasia ectd9 in a pakistani family
BMC Medical Genetics, 2017Co-Authors: Anwar Kamal Khan, Sher Alam Khan, M A Khan, Noor Muhammad, Abdul Aziz, Khadim Shah, Abdul Nasir, Saadullah KhanAbstract:Pure hair and Nail ectodermal Dysplasia (PHNED) is a congenital disorder of hair abnormalities and Nail Dysplasia. Both autosomal recessive and dominant inheritance fashion of PHNED occurs. In literature, to date, five different forms of PHNED have been reported at molecular level, having three genes known and two loci with no gene yet. In this study, a four generations consanguineous family of Pakistani origin with autosomal recessive PHNED was investigated. Affected members exhibited PHNED phenotypes with involvement of complete hair loss and Nail Dysplasia. To screen for mutation in the genes (HOXC13, KRT74, KRT85), its coding exons and exons-intron boundaries were sequenced. The 3D models of normal and mutated HOXC13 were predicted by using homology modeling. Through investigating the family to known loci, the family was mapped to ectodermal Dysplasia 9 (ECTD9) loci with genetic address of 12q13.13. Mutation screening revealed a novel missense mutation (c.929A > C; p.Asn310Thr) in homeobox DNA binding domain of HOXC13 gene in affected members of the family. Due to mutation, loss of hydrogen bonding and difference in potential energy occurs, which may resulting in alteration of protein function. This is the first mutation reported in homeodomain, while 5th mutation reported in HOXC13 gene causing PHNED.
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a novel missense mutation in the gene fzd6 underlies autosomal recessive Nail Dysplasia
British Journal of Dermatology, 2013Co-Authors: Syed Irfan Raza, Saadullah Khan, Noor Muhammad, Wasim AhmadAbstract:Summary Background Inherited isolated Nail anomaly manifesting with onychauxis and onycholysis is a rare condition, caused by mutations in the gene FZD6, encoding membrane-bound Wnt receptor protein. Objectives To search for sequence variants in the gene FZD6 in three individuals of a consanguineous family exhibiting features of Nail Dysplasia. Methods Linkage in the family was searched by genotyping microsatellite markers linked to the gene FZD6, mapped at chromosome 8q22.3. Exons and splice junction sites of the gene FZD6 were polymerase chain reaction amplified and sequenced in an automated DNA sequencer. Results DNA sequence analysis revealed a novel homozygous missense mutation (c.1266G>A; p.Gly422Asp) located in the transmembrane domain of the protein FZD6. Conclusions The missense mutation (p.Gly422Asp), identified here, is only the third mutation detected in the gene FZD6.
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fzd6 encoding the wnt receptor frizzled 6 is mutated in autosomal recessive Nail Dysplasia
British Journal of Dermatology, 2012Co-Authors: Gul Naz, Wasim Ahmad, Sandra M Pasternack, C Perrin, Manuel Mattheisen, Melanie Refke, Saadullah Khan, Asma Gul, M Simons, Regina C BetzAbstract:Summary Background Isolated Nail Dysplasia is rare and has been reported in only a small number of families. Objectives To describe and characterize two Pakistani families with an autosomal-recessive inherited Nail Dysplasia. Methods Genome-wide linkage analysis; mutation screening of candidate genes by Sanger sequencing; cloning of FZD6 and protein analyses; immunohistochemistry. Results We mapped this genodermatosis to chromosome 8q22.3, and identified a homozygous nonsense mutation c.1750G>T (p.E584X) in the frizzled 6 (FZD6) gene in all affected individuals. Immunohistochemical analyses in Nail sections from healthy individuals revealed strong expression of FZD6 in the ventral Nail matrix and a less pronounced expression of FZD6 in the Nail bed. Conclusions FZD6 belongs to a family of proteins that serve as receptors in Wnt signalling pathways, and has been shown to act as a negative regulator of the canonical Wnt/β-catenin signalling cascade and a positive regulator of the noncanonical Wnt or planar cell polarity pathway. The present results therefore suggest that FZD6 plays a pivotal role in the growth and guidance of the Nail plate in humans by acting as a molecular switch between different Wnt pathways. Previous studies have identified mutations in the RSPO4 and LMX1B components of the Wnt pathway in patients with the hypoplastic Nail disorders anonychia and Nail-patella syndrome, respectively. Only recently, FZD6 mutations were identified in isolated Nail Dysplasia. The present results emphasize the important role of the Wnt pathways in Nail development and increase understanding of Wnt-mediated developmental events in general.
Anne-sophie Fröjmark - One of the best experts on this subject based on the ideXlab platform.
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Frizzled6 Deficiency Disrupts the Differentiation Process of Nail Development
The Journal of investigative dermatology, 2013Co-Authors: Chang-yi Cui, Anne-sophie Fröjmark, Joakim Klar, Patrik Georgii-heming, Shahid Mahmood Baig, David Schlessinger, Niklas DahlAbstract:Nails protect the soft tissue of the tips of digits. The molecular mechanism of Nail (and claw) development is largely unknown, but we have recently identified a Wnt receptor gene, Frizzled6 ( Fzd6 ), that is mutated in a human autosomal-recessive Nail Dysplasia. To investigate the action of Fzd6 in claw development at the molecular level, we compared gene expression profiles of digit tips of wild-type and Fzd6 −/- mice, and showed that Fzd6 regulates the transcription of a striking number of epidermal differentiation–related genes. Sixty-three genes encoding keratins (Krts), keratin-associated proteins, and transglutaminases (Tgms) and their substrates were significantly downregulated in the knockout mice. Among them, four hard Krts, Krt86, Krt81, Krt34, and Krt31; two epithelial Krts, Krt6a and Krt6b; and Tgm 1 were already known to be involved in Nail abnormalities when dysregulated. Immunohistochemical studies revealed decreased expression of Krt86, Krt6b, and involucrin in the epidermal portion of the claw field in the knockout embryos. We further showed that Dkk4, a Wnt antagonist, was significantly downregulated in Fzd6 −/- mice along with Wnt, Bmp, and Hh family genes; and Dkk4 transgenic mice showed a subtly but appreciably modified claw phenotype. Thus, Fzd6-mediated Wnt signaling likely regulates the overall differentiation process of Nail/claw formation.
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mutations in frizzled 6 cause isolated autosomal recessive Nail Dysplasia
American Journal of Human Genetics, 2011Co-Authors: Anne-sophie Fröjmark, Jens Schuster, Maria Sobol, Miriam Entesarian, Michaela B C Kilander, Dana Gabrikova, Sadia Nawaz, Shahid Mahmood BaigAbstract:Inherited and isolated Nail malformations are rare and heterogeneous conditions. We identified two consanguineous pedigrees in which some family members were affected by isolated Nail Dysplasia that suggested an autosomal-recessive inheritance pattern and was characterized by claw-shaped Nails, onychauxis, and onycholysis. Genome-wide SNP array analysis of affected individuals from both families showed an overlapping and homozygous region of 800 kb on the long arm of chromosome 8. The candidate region spans eight genes, and DNA sequence analysis revealed homozygous nonsense and missense mutations in FZD(6), the gene encoding Frizzled 6. FZD(6) belongs to a family of highly conserved membrane-bound WNT receptors involved in developmental processes and differentiation through several signaling pathways. We expressed the FZD(6) missense mutation and observed a quantitative shift in subcellular distribution from the plasma membrane to the lysosomes, where the receptor is inaccessible for signaling and presumably degraded. Analysis of human fibroblasts homozygous for the nonsense mutation showed an aberrant response to both WNT-3A and WNT-5A stimulation; this response was consistent with an effect on both canonical and noncanonical WNT-FZD signaling. A detailed analysis of the Fzd(6)(-/-) mice, previously shown to have an altered hair pattern, showed malformed claws predominantly of the hind limbs. Furthermore, a transient Fdz6 mRNA expression was observed in the epidermis of the digital tips at embryonic day 16.5 during early claw morphogenesis. Thus, our combined results show that FZD6 mutations can result in severe defects in Nail and claw formation through reduced or abolished membranous FZD(6) levels and several nonfunctional WNT-FZD pathways.
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Molecular Studies of Diamond-Blackfan Anemia and Congenital Nail Dysplasia
2010Co-Authors: Anne-sophie FröjmarkAbstract:The aim of this thesis is to investigate the effect of genetic mutations on the pathophysiology of two human disorders: Diamond-Blackfan Anemia (DBA) and isolated congenital Nail Dysplasia. The fir ...
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mutations in the frizzled 6 fzd6 gene cause isolated autosomal recessive Nail Dysplasia
2010Co-Authors: Anne-sophie FröjmarkAbstract:The aim of this thesis is to investigate the effect of genetic mutations on the pathophysiology of two human disorders: Diamond-Blackfan Anemia (DBA) and isolated congenital Nail Dysplasia. The first part of this thesis (Paper I-III) investigates the mechanism associated with DBA. DBA is a rare bone marrow failure syndrome characterized by the absence or decrease of erythroid precursor cells. The disease is further associated with growth retardation, malformations, predisposition to malignant disease and heterozygous mutations in ribosomal protein (RP) genes. The second part of this thesis (Paper IV) investigates the genetic basis of isolated autosomal recessive Nail Dysplasia characterized by pachyonychia and onycholysis of both finger- and toeNails. It further dissects the molecular mechanisms regulating Nail development. In the first study, we investigated the previously reported RPS19/PIM-1 interaction by generating a combined Rps19/Pim-1 knockout mouse model. We found that allelic Rps19 insufficiency and Pim-1 deficiency have a cooperative effect on murine hematopoiesis resulting in increased myeloid cellularity associated with cell cycle alterations and reduced apoptosis. In the second study, we analyzed primary fibroblasts from DBA patients with truncating mutations in RPS19 or RPS24 and observed a marked delay in cellular growth associated with specific cell cycle defects. In the third study, we discovered that recombinant RPS19 binds its own mRNA and that the binding is altered when two DBA-associated RPS19 mutations are introduced. In the fourth study, we identified mutations in the WNT signaling receptor Frizzled 6 (FZD6). We observed that the nonsense mutant fails to interact with the first downstream effector Dishevelled. Fzd6 mutant mice displayed claw malformations and we detected a transient Fzd6 expression in the distal digits at the embryonic time point for Nail development. In summary, this thesis elucidates several mechanisms in the etiology of DBA and congenital Nail Dysplasia and mechanisms regulating Nail development.
Shahid Mahmood Baig - One of the best experts on this subject based on the ideXlab platform.
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Frizzled6 Deficiency Disrupts the Differentiation Process of Nail Development
The Journal of investigative dermatology, 2013Co-Authors: Chang-yi Cui, Anne-sophie Fröjmark, Joakim Klar, Patrik Georgii-heming, Shahid Mahmood Baig, David Schlessinger, Niklas DahlAbstract:Nails protect the soft tissue of the tips of digits. The molecular mechanism of Nail (and claw) development is largely unknown, but we have recently identified a Wnt receptor gene, Frizzled6 ( Fzd6 ), that is mutated in a human autosomal-recessive Nail Dysplasia. To investigate the action of Fzd6 in claw development at the molecular level, we compared gene expression profiles of digit tips of wild-type and Fzd6 −/- mice, and showed that Fzd6 regulates the transcription of a striking number of epidermal differentiation–related genes. Sixty-three genes encoding keratins (Krts), keratin-associated proteins, and transglutaminases (Tgms) and their substrates were significantly downregulated in the knockout mice. Among them, four hard Krts, Krt86, Krt81, Krt34, and Krt31; two epithelial Krts, Krt6a and Krt6b; and Tgm 1 were already known to be involved in Nail abnormalities when dysregulated. Immunohistochemical studies revealed decreased expression of Krt86, Krt6b, and involucrin in the epidermal portion of the claw field in the knockout embryos. We further showed that Dkk4, a Wnt antagonist, was significantly downregulated in Fzd6 −/- mice along with Wnt, Bmp, and Hh family genes; and Dkk4 transgenic mice showed a subtly but appreciably modified claw phenotype. Thus, Fzd6-mediated Wnt signaling likely regulates the overall differentiation process of Nail/claw formation.
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mutations in frizzled 6 cause isolated autosomal recessive Nail Dysplasia
American Journal of Human Genetics, 2011Co-Authors: Anne-sophie Fröjmark, Jens Schuster, Maria Sobol, Miriam Entesarian, Michaela B C Kilander, Dana Gabrikova, Sadia Nawaz, Shahid Mahmood BaigAbstract:Inherited and isolated Nail malformations are rare and heterogeneous conditions. We identified two consanguineous pedigrees in which some family members were affected by isolated Nail Dysplasia that suggested an autosomal-recessive inheritance pattern and was characterized by claw-shaped Nails, onychauxis, and onycholysis. Genome-wide SNP array analysis of affected individuals from both families showed an overlapping and homozygous region of 800 kb on the long arm of chromosome 8. The candidate region spans eight genes, and DNA sequence analysis revealed homozygous nonsense and missense mutations in FZD(6), the gene encoding Frizzled 6. FZD(6) belongs to a family of highly conserved membrane-bound WNT receptors involved in developmental processes and differentiation through several signaling pathways. We expressed the FZD(6) missense mutation and observed a quantitative shift in subcellular distribution from the plasma membrane to the lysosomes, where the receptor is inaccessible for signaling and presumably degraded. Analysis of human fibroblasts homozygous for the nonsense mutation showed an aberrant response to both WNT-3A and WNT-5A stimulation; this response was consistent with an effect on both canonical and noncanonical WNT-FZD signaling. A detailed analysis of the Fzd(6)(-/-) mice, previously shown to have an altered hair pattern, showed malformed claws predominantly of the hind limbs. Furthermore, a transient Fdz6 mRNA expression was observed in the epidermis of the digital tips at embryonic day 16.5 during early claw morphogenesis. Thus, our combined results show that FZD6 mutations can result in severe defects in Nail and claw formation through reduced or abolished membranous FZD(6) levels and several nonfunctional WNT-FZD pathways.
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autosomal recessive pure hair and Nail ectodermal Dysplasia linked to chromosome 12p11 1 q14 3 without krthb5 gene mutation
European Journal of Dermatology, 2010Co-Authors: Mahmood Rasool, Joakim Klar, Shahid Mahmood Baig, Sadia Nawaz, Aysha Azhar, Muhammad Wajid, Per Westermark, Niklas DahlAbstract:Hair-Nail ectodermal Dysplasia (HNED; OMIM 602032) constitutes a rare subgroup of ectodermal Dysplasias characterised by onychodystrophy, hypotrichosis and brittle hair. We identified a large consanguineous Pakistani family with four siblings affected by a congenital autosomal recessive form of the disease. Based on previous genetic findings in HNED we performed linkage analysis in the family using chromosome 12 markers. A genetic linkage analysis revealed a lod score of 2.92 ( = 0.0) at locus D12S368, indicating the disease gene to be located on chromosome 12. Candidate genes on chromosome 12, including the KRTHB5 gene and four additional keratin II genes, were sequenced in affected family members. Sequence analysis of the coding regions of keratin KRTHB5 gene, previously associated with a distinct clinical form of hair-Nail Dysplasia, revealed normal coding regions. Our study confirms linkage of a variant clinical form of hair-Nail ectodermal Dysplasia to chromosome 12 without any mutation in the coding sequences of the KRTHB5 gene. The results suggest this family to have either a non-coding mutation in the KRTHB5 gene, or a mutation in a yet unknown gene within the linked region on chromosome 12.
Wasim Ahmad - One of the best experts on this subject based on the ideXlab platform.
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a novel missense mutation in the gene fzd6 underlies autosomal recessive Nail Dysplasia
British Journal of Dermatology, 2013Co-Authors: Syed Irfan Raza, Saadullah Khan, Noor Muhammad, Wasim AhmadAbstract:Summary Background Inherited isolated Nail anomaly manifesting with onychauxis and onycholysis is a rare condition, caused by mutations in the gene FZD6, encoding membrane-bound Wnt receptor protein. Objectives To search for sequence variants in the gene FZD6 in three individuals of a consanguineous family exhibiting features of Nail Dysplasia. Methods Linkage in the family was searched by genotyping microsatellite markers linked to the gene FZD6, mapped at chromosome 8q22.3. Exons and splice junction sites of the gene FZD6 were polymerase chain reaction amplified and sequenced in an automated DNA sequencer. Results DNA sequence analysis revealed a novel homozygous missense mutation (c.1266G>A; p.Gly422Asp) located in the transmembrane domain of the protein FZD6. Conclusions The missense mutation (p.Gly422Asp), identified here, is only the third mutation detected in the gene FZD6.
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fzd6 encoding the wnt receptor frizzled 6 is mutated in autosomal recessive Nail Dysplasia
British Journal of Dermatology, 2012Co-Authors: Gul Naz, Wasim Ahmad, Sandra M Pasternack, C Perrin, Manuel Mattheisen, Melanie Refke, Saadullah Khan, Asma Gul, M Simons, Regina C BetzAbstract:Summary Background Isolated Nail Dysplasia is rare and has been reported in only a small number of families. Objectives To describe and characterize two Pakistani families with an autosomal-recessive inherited Nail Dysplasia. Methods Genome-wide linkage analysis; mutation screening of candidate genes by Sanger sequencing; cloning of FZD6 and protein analyses; immunohistochemistry. Results We mapped this genodermatosis to chromosome 8q22.3, and identified a homozygous nonsense mutation c.1750G>T (p.E584X) in the frizzled 6 (FZD6) gene in all affected individuals. Immunohistochemical analyses in Nail sections from healthy individuals revealed strong expression of FZD6 in the ventral Nail matrix and a less pronounced expression of FZD6 in the Nail bed. Conclusions FZD6 belongs to a family of proteins that serve as receptors in Wnt signalling pathways, and has been shown to act as a negative regulator of the canonical Wnt/β-catenin signalling cascade and a positive regulator of the noncanonical Wnt or planar cell polarity pathway. The present results therefore suggest that FZD6 plays a pivotal role in the growth and guidance of the Nail plate in humans by acting as a molecular switch between different Wnt pathways. Previous studies have identified mutations in the RSPO4 and LMX1B components of the Wnt pathway in patients with the hypoplastic Nail disorders anonychia and Nail-patella syndrome, respectively. Only recently, FZD6 mutations were identified in isolated Nail Dysplasia. The present results emphasize the important role of the Wnt pathways in Nail development and increase understanding of Wnt-mediated developmental events in general.
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Localization of a novel locus for hereditary Nail Dysplasia to chromosome 17q25.1-17q25.3.
Clinical Genetics, 2004Co-Authors: Muhammad Rafiq, Thanh L. Pham, Sayedul Haque, Maria H. Chahrour, Muhammad Ansar, Suzanne M Leal, M. Anwar, M. Amin, Wasim AhmadAbstract:: We report on a six-generation Pakistani consanguineous family with autosomal recessive transmission of a form of hereditary Nail Dysplasia. Affected individuals presented with onycholysis of fingerNails and anonychia of toeNails. Associated abnormalities of ectodermal appendages were not observed in any of the affected individuals. Linkage has been established to chromosome 17q. A maximum multipoint analysis logarithm of the odds ratio score of 4.85 was obtained at marker D17S1301. Due to the consanguineous nature of this kindred, the gene for Nail Dysplasia is probably contained within a 5.0-cM (3 MB on the sequence-based physical map) region of homozygosity flanked by markers D17S1807 and D17S937.
V Dulieu - One of the best experts on this subject based on the ideXlab platform.
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9q33 3q34 11 microdeletion new contiguous gene syndrome encompassing stxbp1 lmx1b and eng genes assessed using reverse phenotyping
European Journal of Human Genetics, 2016Co-Authors: Sophie Nambot, Alice Masurel, Salima El Chehadeh, Annelaure Moscaboidron, Christel Thauvinrobinet, Mathilde Lefebvre, Nathalie Marle, Julien Thevenon, S Perezmartin, V DulieuAbstract:The increasing use of array-CGH in malformation syndromes with intellectual disability could lead to the description of new contiguous gene syndrome by the analysis of the gene content of the microdeletion and reverse phenotyping. Thanks to a national and international call for collaboration by Achropuce and Decipher, we recruited four patients carrying de novo overlapping deletions of chromosome 9q33.3q34.11, including the STXBP1, the LMX1B and the ENG genes. We restrained the selection to these three genes because the effects of their haploinsufficency are well described in the literature and easily recognizable clinically. All deletions were detected by array-CGH and confirmed by FISH. The patients display common clinical features, including intellectual disability with epilepsy, owing to the presence of STXBP1 within the deletion, Nail Dysplasia and bone malformations, in particular patellar abnormalities attributed to LMX1B deletion, epistaxis and cutaneousmucous telangiectasias explained by ENG haploinsufficiency and common facial dysmorphism. This systematic analysis of the genes comprised in the deletion allowed us to identify genes whose haploinsufficiency is expected to lead to disease manifestations and complications that require personalized follow-up, in particular for renal, eye, ear, vascular and neurological manifestations.
