Publications by authors named "Belinda Campos-Xavier"

29 Publications

  • Page 1 of 1

Immune deficiency, autoimmune disease and intellectual disability: A pleiotropic disorder caused by biallelic variants in the TPP2 gene.

Clin Genet 2021 Feb 14. Epub 2021 Feb 14.

Division of Genetic Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

Four individuals from two families presented with a multisystemic condition of suspected genetic origin that was diagnosed only after genome analysis. The main phenotypic features were immune system dysregulation (severe immunodeficiency with autoimmunity) and intellectual disability. The four individuals were found to be homozygous for a 4.4 Kb deletion removing exons 20-23 (NM_003291.4) of the TPP2 gene, predicting a frameshift with premature termination of the protein. The deletion was located on a shared chromosome 13 haplotype indicating a Swiss founder mutation. Tripeptidyl peptidase 2 (TPP2) is a protease involved in HLA/antigen complex processing and amino acid homeostasis. Biallelic variants in TPP2 have been described in 10 individuals with variable features including immune deficiency, autoimmune cytopenias, and intellectual disability or chronic sterile brain inflammation mimicking multiple sclerosis. Our observations further delineate this severe condition not yet included in the OMIM catalog. Timely recognition of TPP2 deficiency is crucial since (1) immune surveillance is needed and hematopoietic stem cell transplantation may be necessary, and (2) for provision of genetic counselling. Additionally, enzyme replacement therapy, as already established for TPP1 deficiency, might be an option in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13942DOI Listing
February 2021

Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator.

Nature 2021 Feb 10. Epub 2021 Feb 10.

Division of Genetic Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.

Long non-coding RNAs (lncRNAs) can be important components in gene-regulatory networks, but the exact nature and extent of their involvement in human Mendelian disease is largely unknown. Here we show that genetic ablation of a lncRNA locus on human chromosome 2 causes a severe congenital limb malformation. We identified homozygous 27-63-kilobase deletions located 300 kilobases upstream of the engrailed-1 gene (EN1) in patients with a complex limb malformation featuring mesomelic shortening, syndactyly and ventral nails (dorsal dimelia). Re-engineering of the human deletions in mice resulted in a complete loss of En1 expression in the limb and a double dorsal-limb phenotype that recapitulates the human disease phenotype. Genome-wide transcriptome analysis in the developing mouse limb revealed a four-exon-long non-coding transcript within the deleted region, which we named Maenli. Functional dissection of the Maenli locus showed that its transcriptional activity is required for limb-specific En1 activation in cis, thereby fine-tuning the gene-regulatory networks controlling dorso-ventral polarity in the developing limb bud. Its loss results in the En1-related dorsal ventral limb phenotype, a subset of the full En1-associated phenotype. Our findings demonstrate that mutations involving lncRNA loci can result in human Mendelian disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-021-03208-9DOI Listing
February 2021

Chondrodysplasia and growth failure in children after early hematopoietic stem cell transplantation for non-oncologic disorders.

Am J Med Genet A 2021 02 4;185(2):517-527. Epub 2021 Jan 4.

Division of Genetic Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

Bone dysplasias (osteochondrodysplasias) are a large group of conditions associated with short stature, skeletal disproportion, and radiographic abnormalities of skeletal elements. Nearly all are genetic in origin. We report a series of seven children with similar findings of chondrodysplasia and growth failure following early hematopoietic stem cell transplantation (HSCT) for pediatric non-oncologic disease: hemophagocytic lymphohistiocytosis or HLH (five children, three with biallelic HLH-associated variants [in PRF1 and UNC13D] and one with HLH secondary to visceral Leishmaniasis), one child with severe combined immunodeficiency and one with Omenn syndrome (both children had biallelic RAG1 pathogenic variants). All children had normal growth and no sign of chondrodysplasia at birth and prior to their primary disease. After HSCT, all children developed growth failure, with standard deviation scores for height at or below -3. Radiographically, all children had changes in the spine, metaphyses and epiphyses, compatible with a spondyloepimetaphyseal dysplasia. Genomic sequencing failed to detect pathogenic variants in genes associated with osteochondrodysplasias. We propose that such chondrodysplasia with growth failure is a novel, rare, but clinically important complication following early HSCT for non-oncologic pediatric diseases. The pathogenesis is unknown but could possibly involve loss or perturbation of the cartilage-bone stem cell population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.62021DOI Listing
February 2021

Osteogenesis imperfecta: towards an individualised interdisciplinary care strategy to improve physical activity and quality of life.

Swiss Med Wkly 2020 Jun 6;150:w20285. Epub 2020 Jul 6.

Paediatric Orthopaedic Unit, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.

Background: This report describes a new strategy for the care of patients with osteogenesis imperfecta, based on an interdisciplinary team working. Thereby, we aim at fulfilling three main goals: offering thorough coordinated management for all, and improving physical activity and quality of life of the patients.

Aim: With rare diseases such as osteogenesis imperfecta (OI), patients and their family often suffer from inadequate recognition of their disease, poor care coordination and incomplete information. A coordinated interdisciplinary approach is one possible solution for providing both comprehensive and cost-effective care, with benefits for patient satisfaction. Poor physical activity and impaired quality of life represent a considerable burden for these patients. To better address these issues, in 2012 we created an interdisciplinary team for the management of OI patients in our University Hospital Centre (CHUV, Lausanne University Hospital,). In this article we describe the implementation of this interdisciplinary care strategy for patients suffering from OI, and its impact on their physical activity and quality of life.

Methods: All patients from the French part of Switzerland were invited to join us. We proposed two complementary evaluations: the initial interdisciplinary evaluation and a yearly follow-up during a special day – the “OI day”. This day features specialised medical appointments adapted to each patient’s needs, as well as lectures and/or workshops dedicated to patients’ and families’ education. Our first aim was to propose for each patient the same management, from diagnosis to the bone health evaluation and physical therapy advice. Our second aim was to evaluate the evolution of physical activity, quality of life (measured by EQ-5D, SF-36 and a dedicated questionnaire) and satisfaction of patients and their families. Here we report both the initial and the long-term results.

Results: Since 2012, 50 patients from the French part of Switzerland received the personalised medical evaluation. All of the patients included in this study had the same initial evaluation and at least one participation in an OI Day. All patients had an adaptation of their bone acting drugs. Over a 7-year period, 62% of inactive patients started some physical activity, and 44% of patients who were not involved in any athletic activity started participating in sports. The mean EQ-5D increased from 0.73 to 0.75 (p = 0.59). The mean physical SF36 (musculoskeletal function) score was 59.09 ± 22.72 and improved to 65.79 ± 21.51 (p = 0.08), whereas it was 68.06 ± 20.05 for the mental SF36 without alteration during follow-up. The OI day was revealed to be useful, it contributed to improvement in continuity of care and helped families to better understand the OI patients’ health.

Conclusions: Our interdisciplinary approach aimed at offering the same thorough management for all patients from the French part of Switzerland, and at improving both the physical activity and the satisfaction of the patients and their family. This report is a basis for future work focusing on the effect of bone fragility and the impact of OI on patients’ social relations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4414/smw.2020.20285DOI Listing
June 2020

The Connective Tissue Disorder Associated with Recessive Variants in the Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases.

Genes (Basel) 2020 04 14;11(4). Epub 2020 Apr 14.

Division of Genetic Medicine, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland.

Recessive loss-of-function variants in a putative zinc transporter gene, were first associated with a connective tissue disorder that is now called "Ehlers-Danlos syndrome, spondylodysplastic form type 3" (SCD-EDS, OMIM 612350) in 2008. Nine individuals have been described. We describe here four additional affected individuals from three consanguineous families and the follow up of two of the original cases. In our series, cardinal findings included thin and finely wrinkled skin of the hands and feet, characteristic facial features with downslanting palpebral fissures, mild hypertelorism, prominent eyes with a paucity of periorbital fat, blueish sclerae, microdontia, or oligodontia, and-in contrast to most types of Ehlers-Danlos syndrome-significant short stature of childhood onset. Mild radiographic changes were observed, among which platyspondyly is a useful diagnostic feature. Two of our patients developed severe keratoconus, and two suffered from cerebrovascular accidents in their twenties, suggesting that there may be a vascular component to this condition. All patients tested had a significantly reduced ratio of the two collagen-derived crosslink derivates, pyridinoline-to-deoxypyridinoline, in urine, suggesting that this simple test is diagnostically useful. Additionally, analysis of the facial features of affected individuals by DeepGestalt technology confirmed their specificity and may be sufficient to suggest the diagnosis directly. Given that the clinical presentation in childhood consists mainly of short stature and characteristic facial features, the differential diagnosis is not necessarily that of a connective tissue disorder and therefore, we propose that is included in gene panels designed to address dysmorphism and short stature. This approach may result in more efficient diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes11040420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231014PMC
April 2020

Severe Peripheral Joint Laxity is a Distinctive Clinical Feature of Spondylodysplastic-Ehlers-Danlos Syndrome (EDS)- and Spondylodysplastic-EDS-.

Genes (Basel) 2019 10 12;10(10). Epub 2019 Oct 12.

Medical Genetics Unit, Maternal and Child Health Department, Azienda USL-IRCCS of Reggio Emilia, 42122 Reggio Emilia, Italy.

Variations in genes encoding for the enzymes responsible for synthesizing the linker region of proteoglycans may result in recessive conditions known as "linkeropathies". The two phenotypes related to mutations in genes and (encoding for galactosyltransferase I and II respectively) are similar, characterized by short stature, hypotonia, joint hypermobility, skeletal features and a suggestive face with prominent forehead, thin soft tissue and prominent eyes. The most outstanding feature of these disorders is the combination of severe connective tissue involvement, often manifesting in newborns and infants, and skeletal dysplasia that becomes apparent during childhood. Here, we intend to more accurately define some of the clinical features of and -related conditions and underline the extreme hypermobility of distal joints and the soft, doughy skin on the hands and feet as features that may be useful as the first clues for a correct diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes10100799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826576PMC
October 2019

The Liberfarb syndrome, a multisystem disorder affecting eye, ear, bone, and brain development, is caused by a founder pathogenic variant in thePISD gene.

Genet Med 2019 12 2;21(12):2734-2743. Epub 2019 Jul 2.

Division of Genetic Medicine, Lausanne University Hospital, Lausanne, Switzerland.

Purpose: We observed four individuals in two unrelated but consanguineous families from Portugal and Brazil affected by early-onset retinal degeneration, sensorineural hearing loss, microcephaly, intellectual disability, and skeletal dysplasia with scoliosis and short stature. The phenotype precisely matched that of an individual of Azorean descent published in 1986 by Liberfarb and coworkers.

Methods: Patients underwent specialized clinical examinations (including ophthalmological, audiological, orthopedic, radiological, and developmental assessment). Exome and targeted sequencing was performed on selected individuals. Minigene constructs were assessed by quantitative polymerase chain reaction (qPCR) and Sanger sequencing.

Results: Affected individuals shared a 3.36-Mb region of autozygosity on chromosome 22q12.2, including a 10-bp deletion (NM_014338.3:c.904-12_904-3delCTATCACCAC), immediately upstream of the last exon of the PISD (phosphatidylserine decarboxylase) gene. Sequencing of PISD from paraffin-embedded tissue from the 1986 case revealed the identical homozygous variant. In HEK293T cells, this variant led to aberrant splicing of PISD transcripts.

Conclusion: We have identified the genetic etiology of the Liberfarb syndrome, affecting brain, eye, ear, bone, and connective tissue. Our work documents the migration of a rare Portuguese founder variant to two continents and highlights the link between phospholipid metabolism and bone formation, sensory defects, and cerebral development, while raising the possibility of therapeutic phospholipid replacement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0595-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892740PMC
December 2019

Peripheral neuropathy and cognitive impairment associated with a novel monoallelic variant.

Ann Clin Transl Neurol 2019 Jun 24;6(6):1072-1080. Epub 2019 May 24.

Division of Genetic Medicine Lausanne University Hospital (CHUV) Lausanne Switzerland.

Background: A 49-year-old male presented with late-onset demyelinating peripheral neuropathy, cerebellar atrophy, and cognitive deficit. Nerve biopsy revealed intra-axonal inclusions suggestive of polyglucosan bodies, raising the suspicion of adult polyglucosan bodies disease (OMIM 263570).

Methods And Results: While known genes associated with polyglucosan bodies storage were negative, whole-exome sequencing identified an unreported monoallelic variant, c.397G>T (p.Val133Phe), in the histidyl-tRNA synthetase () gene. While we did not identify mutations in genes known to be associated with polygucosan body disease, whole-exome sequencing revealed an unreported monoallelic variant, c.397G>T in the histidyl-tRNA synthetase (HARS) gene, encoding a substitution (Val133Phe) in the catalytic domain. Expression of this variant in patient cells resulted in reduced aminoacylation activity in extracts obtained from dermal fibroblasts, without compromising overall protein synthesis.

Interpretation: Genetic variants in the genes coding for the different aminoacyl-tRNA synthases are associated with various clinical conditions. To date, a number of HARS variant have been associated with peripheral neuropathy, but not cognitive deficits. Further studies are needed to explore why HARS mutations confer a neuronal-specific phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562026PMC
June 2019

Identification of novel LFNG mutations in spondylocostal dysostosis.

J Hum Genet 2019 Mar 10;64(3):261-264. Epub 2018 Dec 10.

Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences RIKEN, Tokyo, Japan.

Spondylocostal dysostosis (SCDO) is a heterogeneous group of skeletal disorders characterized by multiple segmentation defects involving vertebrae and ribs. Seven disease genes have been reported as causal genes for SCDO: DLL3, MESP2, TBX6, HES7, RIPPLY2, DMRT2, and LFNG. Here we report a Japanese SCDO case with multiple severe vertebral anomalies from cervical to sacral spine. The patient was a compound heterozygote for c.372delG (p.K124Nfs*) and c.601G>A (p.D201N) variants of LFNG, which encodes a glycosyltransferase (O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase). The missense variant was in the DxD motif, an active-site motif of the glycosyltransferase, and its loss of the enzyme function was confirmed by an in vitro enzyme assay. This is the second report of LFNG mutations in SCDO.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s10038-018-0548-2DOI Listing
March 2019

Lamin B receptor-related disorder is associated with a spectrum of skeletal dysplasia phenotypes.

Bone 2019 03 15;120:354-363. Epub 2018 Nov 15.

Department of Pediatrics, Division of Medical Genetics, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

LBR (Lamin B Receptor) encodes a bifunctional protein important for cholesterol biosynthesis and heterochromatin organization on the inner nuclear membrane. Pathogenic variants in LBR are associated with marked phenotypic variability, ranging from the benign Pelger-Huët anomaly to lethal Greenberg Dysplasia. We performed trio exome sequencing (ES) on two patients with atypical variants of skeletal dysplasia and their unaffected parents. Patient 1 exhibited frontal bossing, mid-face hypoplasia, short stature with rhizomelic limb shortening, and relative macrocephaly at birth. Although remained short, Patient 1 later showed spontaneous improvement in her skeletal findings. Exome sequencing revealed two novel variants in LBR, c.1504C > G (p.Arg502Gly) in exon 12 and c.1748G > T (p.Arg583Leu) in exon 14, which were inherited from her unaffected father and mother, respectively. Sterol analysis revealed an increased level of cholesta‑8,14‑dien‑3β‑ol to 2.9% of total sterols, consistent with a functional deficiency of 3β‑hydroxysterol Δ14‑reductase. Patient 2 presented at birth with short stature and marked rhizomelic limb shortening but later exhibited decreasing severity of shortening of the long bones and improvement in the radiographic skeletal abnormalities although he continued to be significantly short at age 10 years. Exome sequencing revealed that Patient 2 is homozygous for a pathogenic variant c.1534C > T (p.Arg512Trp) in exon 12 of LBR, which was inherited from his unaffected consanguineous parents. This report provides further evidence for a phenotypic spectrum of LBR-associated disorders and expands the genotypic spectrum by describing 3 novel disease-causing variants that have not been previously associated with a disease. Moreover, our data on Patient 1 demonstrate that variants throughout the gene appear to influence both the sterol reductase and nuclear functions of LBR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bone.2018.11.006DOI Listing
March 2019

Progressive pseudorheumatoid dysplasia: a rare childhood disease.

Rheumatol Int 2019 Mar 16;39(3):441-452. Epub 2018 Oct 16.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via della Commenda 9, 20122, Milan, Italy.

Progressive pseudorheumatoid dysplasia (PPRD) is a genetic bone disorder characterised by the progressive degeneration of articular cartilage that leads to pain, stiffness and joint enlargement. As PPRD is a rare disease, available literature is mainly represented by single case reports and only a few larger case series. Our aim is to review the literature concerning clinical, laboratory and radiological features of PPRD. PPRD is due to a mutation in Wnt1-inducible signalling protein 3 (WISP3) gene, which encodes a signalling factor involved in cartilage homeostasis. The disease onset in childhood and skeletal changes progresses over time leading to significant disability. PPRD is a rare condition that should be suspected if a child develops symmetrical polyarticular involvement without systemic inflammation, knobbly interphalangeal joints of the hands, and gait abnormalities. A full skeletal survey, or at least a lateral radiograph of the spine, can direct towards a correct diagnosis that can be confirmed molecularly. More than 70 WISP3 mutations have so far been reported. Genetic testing should start with the study of genomic DNA extracted from blood leucocytes, but intronic mutations in WISP3 causing splicing aberrations can only be detected by analysing WISP3 mRNA, which can be extracted from cultured skin fibroblasts. A skin biopsy is, therefore, indicated in patients with typical PPRD findings and negative mutation screening of genomic DNA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00296-018-4170-6DOI Listing
March 2019

Confirmation of spondylo-epi-metaphyseal dysplasia with joint laxity, EXOC6B type.

Am J Med Genet A 2018 12 4;176(12):2934-2935. Epub 2018 Oct 4.

Division of Genetic Medicine, Lausanne University Hospital (CHUV), University of Lausanne, Lausanne, Switzerland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.40631DOI Listing
December 2018

Hepatosplenomegaly, pneumopathy, bone changes and fronto-temporal dementia: Niemann-Pick type B and SQSTM1-associated Paget's disease in the same individual.

J Bone Miner Metab 2019 Mar 14;37(2):378-383. Epub 2018 Jun 14.

Division of Genetic Medicine, Lausanne University Hospital, Center for Molecular Diseases, Lausanne, Switzerland.

Data from exome sequencing show that a proportion of individuals in whom a genetic disorder is suspected turn out to have not one, but two to four distinct ones. This may require an evolution in our diagnostic attitude towards individuals with complex disorders. We report a patient with splenomegaly, pneumopathy, bone changes and fronto-temporal dementia (FTD). "Sea-blue histiocytes" in his bone marrow pointed to a lysosomal storage disease. Homozygosity for a pathogenic mutation in the SMPD1 gene confirmed Niemann-Pick disease type B (NPD-B). Mild cognitive impairment and abnormal brain FDG PET were consistent with FTD. We initially tried to fit the skeletal and neurologic phenotype into the NPD-B diagnosis. However, additional studies revealed a pathogenic mutation in the SQSTM1 gene. Thus, our patient had two distinct diseases; NPD-B, and Paget's disease of bone with FTD. The subsequent finding of a mutation in SQSTM1 gene ended our struggle to explain the combination of findings by a singular "unifying" diagnosis and allowed us to make specific therapeutic decisions. SQSTM1 mutations have been reported in association with FTD, possibly because of defective autophagy. Bisphosphonates may be beneficial for PDB, but since they are known to inhibit acid sphingomyelinase activity, we refrained from using them in this patient. While the principle of looking for unifying diagnosis remains valid, physicians should consider the possibility of co-existing multiple diagnoses when clinical features are difficult to explain by a single one. Accurate diagnostic work-up can guide genetic counseling but also lead to better medical management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00774-018-0932-1DOI Listing
March 2019

Cortical-Bone Fragility--Insights from sFRP4 Deficiency in Pyle's Disease.

N Engl J Med 2016 Jun;374(26):2553-2562

Background: Cortical-bone fragility is a common feature in osteoporosis that is linked to nonvertebral fractures. Regulation of cortical-bone homeostasis has proved elusive. The study of genetic disorders of the skeleton can yield insights that fuel experimental therapeutic approaches to the treatment of rare disorders and common skeletal ailments.

Methods: We evaluated four patients with Pyle's disease, a genetic disorder that is characterized by cortical-bone thinning, limb deformity, and fractures; two patients were examined by means of exome sequencing, and two were examined by means of Sanger sequencing. After a candidate gene was identified, we generated a knockout mouse model that manifested the phenotype and studied the mechanisms responsible for altered bone architecture.

Results: In all affected patients, we found biallelic truncating mutations in SFRP4, the gene encoding secreted frizzled-related protein 4, a soluble Wnt inhibitor. Mice deficient in Sfrp4, like persons with Pyle's disease, have increased amounts of trabecular bone and unusually thin cortical bone, as a result of differential regulation of Wnt and bone morphogenetic protein (BMP) signaling in these two bone compartments. Treatment of Sfrp4-deficient mice with a soluble Bmp2 receptor (RAP-661) or with antibodies to sclerostin corrected the cortical-bone defect.

Conclusions: Our study showed that Pyle's disease was caused by a deficiency of sFRP4, that cortical-bone and trabecular-bone homeostasis were governed by different mechanisms, and that sFRP4-mediated cross-regulation between Wnt and BMP signaling was critical for achieving proper cortical-bone thickness and stability. (Funded by the Swiss National Foundation and the National Institutes of Health.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070790PMC
http://dx.doi.org/10.1056/NEJMoa1509342DOI Listing
June 2016

NANS-mediated synthesis of sialic acid is required for brain and skeletal development.

Nat Genet 2016 07 23;48(7):777-84. Epub 2016 May 23.

Centre for Molecular Diseases, Lausanne University Hospital (CHUV), University of Lausanne, Lausanne, Switzerland.

We identified biallelic mutations in NANS, the gene encoding the synthase for N-acetylneuraminic acid (NeuNAc; sialic acid), in nine individuals with infantile-onset severe developmental delay and skeletal dysplasia. Patient body fluids showed an elevation in N-acetyl-D-mannosamine levels, and patient-derived fibroblasts had reduced NANS activity and were unable to incorporate sialic acid precursors into sialylated glycoproteins. Knockdown of nansa in zebrafish embryos resulted in abnormal skeletal development, and exogenously added sialic acid partially rescued the skeletal phenotype. Thus, NANS-mediated synthesis of sialic acid is required for early brain development and skeletal growth. Normal sialylation of plasma proteins was observed in spite of NANS deficiency. Exploration of endogenous synthesis, nutritional absorption, and rescue pathways for sialic acid in different tissues and developmental phases is warranted to design therapeutic strategies to counteract NANS deficiency and to shed light on sialic acid metabolism and its implications for human nutrition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3578DOI Listing
July 2016

Brief Report: Peripheral Osteolysis in Adults Linked to ASAH1 (Acid Ceramidase) Mutations: A New Presentation of Farber's Disease.

Arthritis Rheumatol 2016 09 29;68(9):2323-7. Epub 2016 Jul 29.

Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

Objective: To establish a diagnosis and provide counseling and treatment for 3 adult patients from one family presenting with peripheral osteolysis.

Methods: Following clinical and radiographic assessment, exome sequencing, targeted gene resequencing, and determination of enzyme activity in cultured fibroblasts were performed.

Results: The proband (age 40 years) had a history of episodic fever and pain in childhood that subsided around puberty. He and 2 of his older sisters (ages 58 and 60 years, respectively) showed adult-onset progressive shortening of fingers and toes with redundancy of the overlying skin. Radiographs showed severe osteolysis of the distal radius and ulna, carpal bones, metacarpal bones, and phalanges. Sequencing of the known genes for recessively inherited osteolysis, MMP2 and MMP14, failed to show pathogenic mutations. Exome sequencing revealed compound heterozygosity for mutations c.505T>C (p.Trp169Arg) and c.760A>G (p.Arg254Gly) in ASAH1, the gene coding for acid ceramidase. Sanger sequencing confirmed correct segregation in the family, and enzyme activity in fibroblast cultures from the patients was reduced to ∼8% of that in controls, confirming a diagnosis of Farber's disease.

Conclusion: Our findings indicate that hypomorphic mutations in ASAH1 may result in an osteoarticular phenotype with a juvenile phase resembling rheumatoid arthritis that evolves to osteolysis as the final stage in the absence of neurologic signs. This observation delineates a novel type of recessively inherited peripheral osteolysis and illustrates the long-term skeletal manifestations of acid ceramidase deficiency (Farber's disease) in what appear to be the oldest affected individuals known so far.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.39659DOI Listing
September 2016

Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia.

Sci Rep 2015 Nov 24;5:17154. Epub 2015 Nov 24.

Centre for Molecular Diseases, Department of Pediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.

We and others have reported mutations in LONP1, a gene coding for a mitochondrial chaperone and protease, as the cause of the human CODAS (cerebral, ocular, dental, auricular and skeletal) syndrome (MIM 600373). Here, we delineate a similar but distinct condition that shares the epiphyseal, vertebral and ocular changes of CODAS but also included severe microtia, nasal hypoplasia, and other malformations, and for which we propose the name of EVEN-PLUS syndrome for epiphyseal, vertebral, ear, nose, plus associated findings. In three individuals from two families, no mutation in LONP1 was found; instead, we found biallelic mutations in HSPA9, the gene that codes for mHSP70/mortalin, another highly conserved mitochondrial chaperone protein essential in mitochondrial protein import, folding, and degradation. The functional relationship between LONP1 and HSPA9 in mitochondrial protein chaperoning and the overlapping phenotypes of CODAS and EVEN-PLUS delineate a family of "mitochondrial chaperonopathies" and point to an unexplored role of mitochondrial chaperones in human embryonic morphogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep17154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657157PMC
November 2015

NBAS mutations cause a multisystem disorder involving bone, connective tissue, liver, immune system, and retina.

Am J Med Genet A 2015 Dec 19;167A(12):2902-12. Epub 2015 Aug 19.

Center for Molecular Diseases, Lausanne University Hospital, Lausanne, Switzerland.

We report two unrelated patients with a multisystem disease involving liver, eye, immune system, connective tissue, and bone, caused by biallelic mutations in the neuroblastoma amplified sequence (NBAS) gene. Both presented as infants with recurrent episodes triggered by fever with vomiting, dehydration, and elevated transaminases. They had frequent infections, hypogammaglobulinemia, reduced natural killer cells, and the Pelger-Huët anomaly of their granulocytes. Their facial features were similar with a pointed chin and proptosis; loose skin and reduced subcutaneous fat gave them a progeroid appearance. Skeletal features included short stature, slender bones, epiphyseal dysplasia with multiple phalangeal pseudo-epiphyses, and small C1-C2 vertebrae causing cervical instability and myelopathy. Retinal dystrophy and optic atrophy were present in one patient. NBAS is a component of the synthaxin-18 complex and is involved in nonsense-mediated mRNA decay control. Putative loss-of-function mutations in NBAS are already known to cause disease in humans. A specific founder mutation has been associated with short stature, optic nerve atrophy and Pelger-Huët anomaly of granulocytes (SOPH) in the Siberian Yakut population. A more recent report associates NBAS mutations with recurrent acute liver failure in infancy in a group of patients of European descent. Our observations indicate that the phenotypic spectrum of NBAS deficiency is wider than previously known and includes skeletal, hepatic, metabolic, and immunologic aspects. Early recognition of the skeletal phenotype is important for preventive management of cervical instability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.37338DOI Listing
December 2015

Mutations in LONP1, a mitochondrial matrix protease, cause CODAS syndrome.

Am J Med Genet A 2015 Jul 21;167(7):1501-9. Epub 2015 Mar 21.

Medical Genetics Service, CHUV, University of Lausanne, Switzerland.

Cerebral, ocular, dental, auricular, skeletal anomalies (CODAS) syndrome (MIM 600373) was first described and named by Shehib et al, in 1991 in a single patient. The anomalies referred to in the acronym are as follows: cerebral-developmental delay, ocular-cataracts, dental-aberrant cusp morphology and delayed eruption, auricular-malformations of the external ear, and skeletal-spondyloepiphyseal dysplasia. This distinctive constellation of anatomical findings should allow easy recognition but despite this only four apparently sporadic patients have been reported in the last 20 years indicating that the full phenotype is indeed very rare with perhaps milder or a typical presentations that are allelic but without sufficient phenotypic resemblance to permit clinical diagnosis. We performed exome sequencing in three patients (an isolated case and a brother and sister sib pair) with classical features of CODAS. Sanger sequencing was used to confirm results as well as for mutation discovery in a further four unrelated patients ascertained via their skeletal features. Compound heterozygous or homozygous mutations in LONP1 were found in all (8 separate mutations; 6 missense, 1 nonsense, 1 small in-frame deletion) thus establishing the genetic basis of CODAS and the pattern of inheritance (autosomal recessive). LONP1 encodes an enzyme of bacterial ancestry that participates in protein turnover within the mitochondrial matrix. The mutations cluster at the ATP-binding and proteolytic domains of the enzyme. Biallelic inheritance and clustering of mutations confirm dysfunction of LONP1 activity as the molecular basis of CODAS but the pathogenesis remains to be explored.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.37029DOI Listing
July 2015

Positive effects of an angiotensin II type 1 receptor antagonist in Camurati-Engelmann disease: a single case observation.

Am J Med Genet A 2014 Oct 5;164A(10):2667-71. Epub 2014 Aug 5.

Unit of Pediatric Genetics Department of Pediatrics, Hacettepe University Medical Faculty, Ankara, Turkey; Division of Molecular Pediatrics Department of Pediatrics, University of Lausanne, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

Camurati-Engelmann disease is characterized by hyperostosis of the long bones and the skull, muscle atrophy, severe limb pain, and progressive joint contractures in some patients. It is caused by heterozygous mutations in the transforming growth factor β1 (TGFβ1) believed to result in improper folding of the latency-associated peptide domain of TGFβ1 and thus in increased or deregulated bioactivity. Losartan, an angiotensin II type 1 receptor antagonist, has been found to downregulate the expression of TGFβ type 1 and 2 receptors. Clinical trials with losartan have shown a benefit in Marfan syndrome, while trials are underway for Duchenne muscular dystrophy and other myopathies associated with TGFβ1 signaling. We hypothesized that due to its anti-TGFβ1 activity, losartan might be beneficial in Camurati-Engelmann disease. This report concerns a boy who presented at age 13 years with severe limb pain and difficulty in walking. Clinical and radiographic evaluation results were compatible with Camurati-Engelmann disease and the diagnosis was confirmed by mutation analysis (c.652C > T [p.Arg218Cys]). The boy underwent an experimental treatment with losartan at a dosage of 50 mg/day, orally. During the treatment period of 18 months, the intensity and frequency of limb pain decreased significantly (as shown by a pain diary), and muscle strength improved, allowing the boy to resume walking and climbing stairs. No obvious side effects were observed. We cautiously conclude that TGFβ1 inhibition with losartan deserves further evaluation in the clinical management of Camurati-Engelmann disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.36692DOI Listing
October 2014

[Genetics of childhood epilepsies: for who? how? why?].

Rev Med Suisse 2014 Jan;10(412-413):110-1

Unité de Neuropédiatrie et Neuroréhabelitation Pédiatrique, CHUV, Lausanne.

Recent advances in genetics led to significant improvement in the field of childhood epilepsies diagnosis and physiopathology. Genetic testing is indicated by geneticist who is himself guided by the pediatric neurological approach. In rare circumstance, genetic etiology affects the clinical management. Cost remains the main limitation. Those new genetic tools are the first step toward a better understanding of seizure mechanism and therefore more efficient treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
January 2014

Homozygosity for a novel truncating mutation confirms TBX15 deficiency as the cause of Cousin syndrome.

Am J Med Genet A 2013 Dec 16;161A(12):3161-5. Epub 2013 Aug 16.

Division of Molecular Pediatrics, Department of Pediatrics, University of Lausanne, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

Cousin syndrome, also called pelviscapular dysplasia (OMIM 260660), is characterized by short stature, craniofacial dysmorphism, and multiple skeletal anomalies. Following its description in two sibs in 1982, no new cases have been observed until the observation of two unrelated cases in 2008 who were homozygous for frameshift mutations in TBX15. We investigated an adult individual with short stature, a complex craniofacial dysmorphism, malformed and rotated ears, short neck, elbow contractures, hypoacusis, and hypoplasia of scapula and pelvis on radiographs. We identified homozygosity for a novel nonsense mutation (c.841C>T) in TBX15 predicted to cause a premature stop (p.Arg281*) with truncation of the protein. This observation confirms that Cousin syndrome is a consistent and clinically recognizable phenotype caused by loss of function of TBX15.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.36173DOI Listing
December 2013

FAM111A mutations result in hypoparathyroidism and impaired skeletal development.

Am J Hum Genet 2013 Jun 16;92(6):990-5. Epub 2013 May 16.

Department of Pediatrics, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland; Medical Genetics Service, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland.

Kenny-Caffey syndrome (KCS) and the similar but more severe osteocraniostenosis (OCS) are genetic conditions characterized by impaired skeletal development with small and dense bones, short stature, and primary hypoparathyroidism with hypocalcemia. We studied five individuals with KCS and five with OCS and found that all of them had heterozygous mutations in FAM111A. One mutation was identified in four unrelated individuals with KCS, and another one was identified in two unrelated individuals with OCS; all occurred de novo. Thus, OCS and KCS are allelic disorders of different severity. FAM111A codes for a 611 amino acid protein with homology to trypsin-like peptidases. Although FAM111A has been found to bind to the large T-antigen of SV40 and restrict viral replication, its native function is unknown. Molecular modeling of FAM111A shows that residues affected by KCS and OCS mutations do not map close to the active site but are clustered on a segment of the protein and are at, or close to, its outer surface, suggesting that the pathogenesis involves the interaction with as yet unidentified partner proteins rather than impaired catalysis. FAM111A appears to be crucial to a pathway that governs parathyroid hormone production, calcium homeostasis, and skeletal development and growth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2013.04.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675238PMC
June 2013

Recurrent dominant mutations affecting two adjacent residues in the motor domain of the monomeric kinesin KIF22 result in skeletal dysplasia and joint laxity.

Am J Hum Genet 2011 Dec;89(6):767-72

Children's Hospital Boston, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.

Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type (lepto-SEMDJL, aka SEMDJL, Hall type), is an autosomal dominant skeletal disorder that, in spite of being relatively common among skeletal dysplasias, has eluded molecular elucidation so far. We used whole-exome sequencing of five unrelated individuals with lepto-SEMDJL to identify mutations in KIF22 as the cause of this skeletal condition. Missense mutations affecting one of two adjacent amino acids in the motor domain of KIF22 were present in 20 familial cases from eight families and in 12 other sporadic cases. The skeletal and connective tissue phenotype produced by these specific mutations point to functions of KIF22 beyond those previously ascribed functions involving chromosome segregation. Although we have found Kif22 to be strongly upregulated at the growth plate, the precise pathogenetic mechanisms remain to be elucidated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2011.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234368PMC
December 2011

Whole-exome sequencing detects somatic mutations of IDH1 in metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA).

Am J Med Genet A 2011 Nov;155A(11):2609-16

Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Nijmegen, Netherlands.

We used exome sequencing of blood DNA in four unrelated patients to identify the genetic basis of metaphyseal chondromatosis with urinary excretion of D-2-hydroxy-glutaric acid (MC-HGA), a rare entity comprising severe chondrodysplasia, organic aciduria, and variable cerebral involvement. No evidence for recessive mutations was found; instead, two patients showed mutations in IDH1 predicting p.R132H and p.R132S as apparent somatic mosaicism. Sanger sequencing confirmed the presence of the mutation in blood DNA in one patient, and in blood and saliva (but not in fibroblast) DNA in the other patient. Mutations at codon 132 of IDH1 change the enzymatic specificity of the cytoplasmic isocitrate dehydrogenase enzyme. They result in increased D-2-hydroxy-glutarate production, α-ketoglutarate depletion, activation of HIF-1α (a key regulator of chondrocyte proliferation at the growth plate), and reduction of N-acetyl-aspartyl-glutamate level in glial cells. Thus, somatic mutations in IDH1 may explain all features of MC-HGA, including sporadic occurrence, metaphyseal disorganization, and chondromatosis, urinary excretion of D-2-hydroxy-glutaric acid, and reduced cerebral myelinization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.34325DOI Listing
November 2011

Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.

PLoS Genet 2011 Apr 14;7(4):e1002050. Epub 2011 Apr 14.

Department of Orthopaedic Surgery, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts, United States of America.

Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a "second hit," that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1002050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077396PMC
April 2011

Evolutionary comparison provides evidence for pathogenicity of RMRP mutations.

PLoS Genet 2005 Oct;1(4):e47

Division of Molecular Pediatrics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

Cartilage-hair hypoplasia (CHH) is a pleiotropic disease caused by recessive mutations in the RMRP gene that result in a wide spectrum of manifestations including short stature, sparse hair, metaphyseal dysplasia, anemia, immune deficiency, and increased incidence of cancer. Molecular diagnosis of CHH has implications for management, prognosis, follow-up, and genetic counseling of affected patients and their families. We report 20 novel mutations in 36 patients with CHH and describe the associated phenotypic spectrum. Given the high mutational heterogeneity (62 mutations reported to date), the high frequency of variations in the region (eight single nucleotide polymorphisms in and around RMRP), and the fact that RMRP is not translated into protein, prediction of mutation pathogenicity is difficult. We addressed this issue by a comparative genomic approach and aligned the genomic sequences of RMRP gene in the entire class of mammals. We found that putative pathogenic mutations are located in highly conserved nucleotides, whereas polymorphisms are located in non-conserved positions. We conclude that the abundance of variations in this small gene is remarkable and at odds with its high conservation through species; it is unclear whether these variations are caused by a high local mutation rate, a failure of repair mechanisms, or a relaxed selective pressure. The marked diversity of mutations in RMRP and the low homozygosity rate in our patient population indicate that CHH is more common than previously estimated, but may go unrecognized because of its variable clinical presentation. Thus, RMRP molecular testing may be indicated in individuals with isolated metaphyseal dysplasia, anemia, or immune dysregulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.0010047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1262189PMC
October 2005

Homozygosity mapping of a Weill-Marchesani syndrome locus to chromosome 19p13.3-p13.2.

Hum Genet 2002 Apr 13;110(4):366-70. Epub 2002 Mar 13.

Département de Génétique et INSERM U393, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, 75015 Paris, France.

Weill-Marchesani syndrome (WMS) is a rare disease characterized by short stature, brachydactyly, joint stiffness, and characteristic eye abnormalities, including microspherophakia, ectopia lentis, and glaucoma. Both autosomal recessive and autosomal dominant modes of inheritance have been described in association with WMS. We have performed a genome-wide search in two large consanguineous families of Lebanese and Saudian origin consistent with an autosomal recessive mode of inheritance. Here, we report the linkage of the disease gene to chromosome 19p13.3-p13.2 (Zmax=5.99 at theta=0 at locus D19S906). A recombination event between loci D19S905 and D19S901 defines the distal boundary, and a second recombination event between loci D19S221 and D19S840 defines the proximal boundary of the genetic interval encompassing the WMS gene (12.4 cM). We hope that our ongoing studies will lead to the identification of the disease-causing gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00439-002-0689-3DOI Listing
April 2002