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1.
Biochem Pharmacol ; 185: 114452, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33545117

RESUMO

Diastrophic dysplasia (DTD) is a recessive chondrodysplasia caused by mutations in the SLC26A2 gene encoding for a sulfate/chloride transporter. When SLC26A2 is impaired intracellular level of sulfate is reduced leading to the synthesis of undersulfated proteoglycans. In normal chondrocytes, the main source of intracellular sulfate is the extracellular uptake through SLC26A2, but a small amount comes from the catabolism of sulfur-containing amino acids and other thiols. Here N-acetylcysteine (NAC), an extensively used drug, is proposed as alternative source of intracellular sulfate in an animal model of DTD (dtd mouse). Mutant and wild type mice were treated twice a day with hypodermic injections of 250 mg NAC/kg body weight for one week after birth. At the end of the treatment, an improvement trend in cartilage proteoglycan sulfation and in the skeletal phenotype of treated dtd mice were observed. Thus, a longer treatment lasted three weeks starting from birth was performed. Treated mutant mice showed a significant increase of cartilage proteoglycan sulfation and a relevant improvement of the skeletal phenotype based on measurements of several bony elements and bone quality by DEXA and micro CT. Moreover, the amelioration of the overall growth plate morphology in treated dtd mice suggested a partial rescue of the endochondral ossification process. Overall, the results prove that NAC is an effective source of intracellular sulfate for dtd mice in the postnatal period. This finding paves the way for a potential pharmacological treatment of DTD patients taking advantage from a drug repositioning strategy.

2.
Clin Genet ; 2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33586135

RESUMO

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.

3.
Eur J Hum Genet ; 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594261

RESUMO

Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the central nervous system, heart, kidney, and other organs. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels is well known, GOF missense variants in K+ channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized. These syndromic phenotypes include Zimmermann-Laband and Temple-Baraitser syndromes, caused by dominant variants in KCNH1, FHEIG syndrome due to dominant variants in KCNK4, and the clinical picture associated with dominant variants in KCNN3. Here we review the presentation of these individuals, including five newly reported with variants in KCNH1 and three additional individuals with KCNN3 variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant KCNN3, KCNH1, and KCNK4 variants, sharing developmental delay and/or ID, coarse facial features, gingival enlargement, distal digital hypoplasia, and hypertrichosis. We suggest to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K+ conductance, referred to as syndromic neurodevelopmental K+ channelopathies due to dominant variants in KCNH1, KCNK4, or KCNN3.

4.
Nature ; 592(7852): 93-98, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33568816

RESUMO

Long non-coding RNAs (lncRNAs) can be important components in gene-regulatory networks1, 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.


Assuntos
Extremidades , Proteínas de Homeodomínio/genética , Deformidades Congênitas dos Membros/genética , RNA Longo não Codificante/genética , Deleção de Sequência/genética , Transcrição Genética , Ativação Transcricional/genética , Animais , Linhagem Celular , Cromatina/genética , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Transgênicos
6.
J Med Genet ; 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397746

RESUMO

BACKGROUND: Next-generation sequencing, combined with international pooling of cases, has impressively enhanced the discovery of genes responsible for Mendelian neurodevelopmental disorders, particularly in individuals affected by clinically undiagnosed diseases. To date, biallelic missense variants in ZNF526 gene, encoding a Krüppel-type zinc-finger protein, have been reported in three families with non-syndromic intellectual disability. METHODS: Here, we describe five individuals from four unrelated families with an undiagnosed neurodevelopmental disorder in which we performed exome sequencing, on a combination of trio-based (4 subjects) or single probands (1 subject). RESULTS: We identified five patients from four unrelated families with homozygous ZNF526 variants by whole exome sequencing. Four had variants resulting in truncation of ZNF526; they were affected by severe prenatal and postnatal microcephaly (ranging from -4 SD to -8 SD), profound psychomotor delay, hypertonic-dystonic movements, epilepsy and simplified gyral pattern on MRI. All of them also displayed bilateral progressive cataracts. A fifth patient had a homozygous missense variant and a slightly less severe disorder, with postnatal microcephaly (-2 SD), progressive bilateral cataracts, severe intellectual disability and unremarkable brain MRI.Mutant znf526 zebrafish larvae had notable malformations of the eye and central nervous system, resembling findings seen in the human holoprosencephaly spectrum. CONCLUSION: Our findings support the role of ZNF526 biallelic variants in a complex neurodevelopmental disorder, primarily affecting brain and eyes, resulting in severe microcephaly, simplified gyral pattern, epileptic encephalopathy and bilateral cataracts.

7.
Nat Commun ; 12(1): 518, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33483490

RESUMO

Homozygosity mapping is a powerful method for identifying mutations in patients with recessive conditions, especially in consanguineous families or isolated populations. Historically, it has been used in conjunction with genotypes from highly polymorphic markers, such as DNA microsatellites or common SNPs. Traditional software performs rather poorly with data from Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS), which are now extensively used in medical genetics. We develop AutoMap, a tool that is both web-based or downloadable, to allow performing homozygosity mapping directly on VCF (Variant Call Format) calls from WES or WGS projects. Following a training step on WES data from 26 consanguineous families and a validation procedure on a matched cohort, our method shows higher overall performances when compared with eight existing tools. Most importantly, when tested on real cases with negative molecular diagnosis from an internal set, AutoMap detects three gene-disease and multiple variant-disease associations that were previously unrecognized, projecting clear benefits for both molecular diagnosis and research activities in medical genetics.


Assuntos
Mapeamento Cromossômico/métodos , Biologia Computacional/métodos , Genoma Humano/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Polimorfismo de Nucleotídeo Único , Software , Predisposição Genética para Doença/genética , Genótipo , Homozigoto , Humanos , Internet , Mutação , Reprodutibilidade dos Testes , Sequenciamento Completo do Exoma/métodos
8.
Am J Med Genet A ; 185(2): 517-527, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33398909

RESUMO

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.

9.
Rev Med Suisse ; 16(718): 2387-2390, 2020 Dec 09.
Artigo em Francês | MEDLINE | ID: mdl-33300699

RESUMO

Congenital venous malformations (VMs) are the most common vascular abnormalities. Their treatment can be complex, depending on their size and surrounding tissues involvement. To date, sclerotherapy is considered the gold standard for the treatment of VMs. This technique, which aims to destroy the endothelium and thus cause fibrosis and retraction of the vascular lesion, is less effective in voluminous VMs. Endovenous thermal ablation is a widely validated treatment in the management of venous insufficiency, showing better efficacy than sclerotherapy in terms of trans-parietal vessel destruction. This approach has therefore also been described in the treatment of VMs. This technique has been introduced for the treatment of complex VMs at the Centre for Malformations and Rare Vascular Diseases of the CHUV.

10.
Orphanet J Rare Dis ; 15(1): 210, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32811506

RESUMO

BACKGROUND: Inherited metabolic diseases (IMD) are complex medical conditions. Thanks to improvements in diagnosis and treatment, a growing number of pediatric IMD patients reach adulthood. Thus, clinical care of adults with IMD has emerged as a new and challenging reality. This purpose of this study of adults with IMD in an adult metabolic clinic at two academic hospitals (Lausanne and Geneva) was to help inform decisions on the future organization of health care for this group of patients. METHODS: All adult patients with a biochemical and/or genetic diagnosis of IMD followed at the clinics were included in the study. Electronic patient records were reviewed for clinical features, diagnostic studies, treatment and long-term outcome. Data of undiagnosed patients referred for suspected IMD were analyzed separately. RESULTS: 126 patients were included in the study. The most prevalent group of diseases was small molecules disorders with 82 (65%) patients, followed by energy defects disorders with 29 (23%) patients and complex molecules disorders with 15 (12%) patients. Overall, 64% of patients were diagnosed before, and 36% after the age 16 years. Among the 126 cases, 51% suffered from medical complications. 79% of the patients were receiving a specific treatment for their disease. Among the 138 undiagnosed patients referred for suspicion of IMD, investigations lead to a genetic diagnosis in 24 (17%) patients. 19 had confirmation of an IMD, 5 were found to have another genetic condition. CONCLUSIONS: This retrospective study reveals significant features of adult IMD cohort. The disorders are heterogeneous, and there is no one-size-fits-all approach - treatment must be tailored to fit each specific disorder in each individual patient. Even patients who are followed at the dedicated clinic are not protected from metabolic decompensations and/or chronic organ-specific complications. While it is commonly assumed that patients with IMD are more stable once they become adults, our data show that the diseases continue to exact a lifelong toll. A coordinated monitoring of target organs by a multidisciplinary team is needed. To ensure that the success in diagnosis and treatment of individuals with IMD is sustained, there is a clear requirement for adequately staffed adult IMD clinics.

11.
J Hum Genet ; 65(11): 1035-1038, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32555312

RESUMO

Non-invasive prenatal testing (NIPT) is increasingly used in routine practice due to its high sensitivity and specificity in detecting fetal chromosomal anomalies. Several reports have highlighted that NIPT can diagnose previously unsuspected malignancy or benign copy number variation in the expectant mother. We report a case in which NIPT detected a duplication involving the 17p11.2-17p12 region with possible Potocki-Lupski syndrome in the fetus. However, on further questioning, the mother revealed that she had Charcot-Marie-Tooth neuropathy type IA (CMT1A) and thus using array CGH, we were able to confirm that the 17p duplication was maternal in origin, included only the typical CMT1A region and that the fetus had a normal chromosome complement. Although it may be rare for a mother to have a pathogenic chromosome duplication/deletion, with the expansion in scope of NIPT from classic trisomies to global chromosome coverage and monogenic conditions, more examples of fortuitous maternal diagnosis will certainly be forthcoming and this should be taken into account during pre-test genetic counseling.

12.
Rev Med Suisse ; 16(696): 1148-1152, 2020 Jun 03.
Artigo em Francês | MEDLINE | ID: mdl-32496703

RESUMO

The gene SCN5A encodes the cardiac sodium channel which, through the conduction of Na+ current into the cell, generates the fast upstroke of the action potential of cardiomyocytes. Pathogenic variants of SCN5A have been causally associated to several hereditary cardiac diseases including, among others, Brugada syndrome, congenital long QT syndrome and sinus node dysfunction. Recently, overlap syndromes have been described that are characterized by the simultaneous expression of mixed clinical phenotypes among two or more hereditary cardiac diseases associated to the gene SCN5A (HCD-SCN5A). For this reason, it is time to rethink about HCD-SCN5A as different expressions of the same complex spectrum encompassing multiple clinical phenotypes with pronounced overlaps instead of as distinct clinical entities.


Assuntos
Síndrome de Brugada , Síndrome do QT Longo , Síndrome do Nó Sinusal , Síndrome de Brugada/genética , Humanos , Síndrome do QT Longo/genética , Mutação , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Fenótipo , Síndrome do Nó Sinusal/genética , Síndrome
13.
Hum Mol Genet ; 29(13): 2250-2260, 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32533184

RESUMO

We investigated the genetic origin of the phenotype displayed by three children from two unrelated Italian families, presenting with a previously unrecognized autosomal recessive disorder that included a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and Leber congenital amaurosis (SHILCA), as well as some brain anomalies that were visible at the MRI. Autozygome-based analysis showed that these children shared a 4.76 Mb region of homozygosity on chromosome 1, with an identical haplotype. Nonetheless, whole-exome sequencing failed to identify any shared rare coding variants, in this region or elsewhere. We then determined the transcriptome of patients' fibroblasts by RNA sequencing, followed by additional whole-genome sequencing experiments. Gene expression analysis revealed a 4-fold downregulation of the gene NMNAT1, residing indeed in the shared autozygous interval. Short- and long-read whole-genome sequencing highlighted a duplication involving 2 out of the 5 exons of NMNAT1 main isoform (NM_022787.3), leading to the production of aberrant mRNAs. Pathogenic variants in NMNAT1 have been previously shown to cause non-syndromic Leber congenital amaurosis (LCA). However, no patient with null biallelic mutations has ever been described, and murine Nmnat1 knockouts show embryonic lethality, indicating that complete absence of NMNAT1 activity is probably not compatible with life. The rearrangement found in our cases, presumably causing a strong but not complete reduction of enzymatic activity, may therefore result in an intermediate syndromic phenotype with respect to LCA and lethality.

14.
Dev Cell ; 53(4): 418-430.e4, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32428455

RESUMO

Capillary morphogenesis gene 2 (CMG2/ANTXR2) is a cell surface receptor for both collagen VI and anthrax toxin. Biallelic loss-of-function mutations in CMG2 lead to a severe condition, hyaline fibromatosis syndrome (HFS). We have here dissected a network of dynamic interactions between CMG2 and various actin interactors and regulators, describing a different behavior from other extracellular matrix receptors. CMG2 binds talin, and thereby the actin cytoskeleton, only in its ligand-free state. Extracellular ligand binding leads to src-dependent talin release and recruitment of the actin cytoskeleton regulator RhoA and its effectors. These sequential interactions of CMG2 are necessary for the control of oriented cell division during fish development. Finally, we demonstrate that effective switching between talin and RhoA binding is required for the intracellular degradation of collagen VI in human fibroblasts, which explains why HFS mutations in the cytoskeleton-binding domain lead to dysregulation of extracellular matrix homeostasis.

15.
Genes (Basel) ; 11(4)2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32295219

RESUMO

Recessive loss-of-function variants in SLC39A13, 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 SLC39A13 is included in gene panels designed to address dysmorphism and short stature. This approach may result in more efficient diagnosis.

16.
Int J Mol Sci ; 21(8)2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32295296

RESUMO

Proteoglycans (PGs) are macromolecules present on the cell surface and in the extracellular matrix that confer specific mechanical, biochemical, and physical properties to tissues. Sulfate groups present on glycosaminoglycans, linear polysaccharide chains attached to PG core proteins, are fundamental for correct PG functions. Indeed, through the negative charge of sulfate groups, PGs interact with extracellular matrix molecules and bind growth factors regulating tissue structure and cell behavior. The maintenance of correct sulfate metabolism is important in tissue development and function, particularly in cartilage where PGs are fundamental and abundant components of the extracellular matrix. In chondrocytes, the main sulfate source is the extracellular space, then sulfate is taken up and activated in the cytosol to the universal sulfate donor to be used in sulfotransferase reactions. Alteration in each step of sulfate metabolism can affect macromolecular sulfation, leading to the onset of diseases that affect mainly cartilage and bone. This review presents a panoramic view of skeletal dysplasias caused by mutations in genes encoding for transporters or enzymes involved in macromolecular sulfation. Future research in this field will contribute to the understanding of the disease pathogenesis, allowing the development of targeted therapies aimed at alleviating, preventing, or modifying the disease progression.

17.
Mol Genet Genomic Med ; 8(6): e1203, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32196989

RESUMO

BACKGROUND: Hyaline fibromatosis syndrome is an autosomal recessive disease caused by mutations in ANTXR2 which leads to loss of function of the transmembrane protein anthrax toxin receptor 2. It is distinguished by characteristic skin lesions, gingival hyperplasia, joint and bone disease, and systemic involvement. METHODS: Based on the case of an 11-year-old female patient with typical features of hyaline fibromatosis syndrome and the underlying pathogenic compound heterozygote variants in ANTXR2 we discuss the genetic and clinical aspects of hyaline fibromatosis syndrome. RESULTS: The novel mutation in ANTXR2 (c.1223T>C, p.Leu408Pro variant) seems to allow for a protracted course of the disease. CONCLUSION: Our findings add to the phenotypic, genetic, and biochemical spectrum of hyaline fibromatosis syndrome.

18.
BMC Neurol ; 20(1): 17, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31931739

RESUMO

BACKGROUND: A new monogenic neurodegenerative disease affecting ribosomal metabolism has recently been identified in association with a monoallelic UBTF putative gain of function variant (NM_001076683.1:c.628G>A, hg19). Phenotype is consistent among these probands with progressive motor, cognitive, and behavioural regression in early to middle childhood. CASE PRESENTATION: We report on a child with this monoallelic UBTF variant who presented with progressive disease including regression, episodes of subacute deterioration during febrile illnesses and a remarkable EEG pattern with a transient pattern of semi-periodic slow waves. CONCLUSIONS: This case further supports the phenotype-genotype correlation of neurodegeneration associated with UBTF c.628G>A. Moreover, it brings new insights into the clinical features and EEG that could possibly serve as diagnostic markers of this otherwise nonspecific phenotype.


Assuntos
Doenças Neurodegenerativas/genética , Proteínas Pol1 do Complexo de Iniciação de Transcrição/genética , Criança , Variação Genética , Genótipo , Humanos , Masculino , Fenótipo
19.
Hum Mutat ; 41(3): 655-667, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31705726

RESUMO

Congenital disorders of glycosylation (CDGs) comprise a large number of inherited metabolic defects that affect the biosynthesis and attachment of glycans. CDGs manifest as a broad spectrum of disease, most often including neurodevelopmental and skeletal abnormalities and skin laxity. Two patients with biallelic CSGALNACT1 variants and a mild skeletal dysplasia have been described previously. We investigated two unrelated patients presenting with short stature with advanced bone age, facial dysmorphism, and mild language delay, in whom trio-exome sequencing identified novel biallelic CSGALNACT1 variants: compound heterozygosity for c.1294G>T (p.Asp432Tyr) and the deletion of exon 4 that includes the start codon in one patient, and homozygosity for c.791A>G (p.Asn264Ser) in the other patient. CSGALNACT1 encodes CSGalNAcT-1, a key enzyme in the biosynthesis of sulfated glycosaminoglycans chondroitin and dermatan sulfate. Biochemical studies demonstrated significantly reduced CSGalNAcT-1 activity of the novel missense variants, as reported previously for the p.Pro384Arg variant. Altered levels of chondroitin, dermatan, and heparan sulfate moieties were observed in patients' fibroblasts compared to controls. Our data indicate that biallelic loss-of-function mutations in CSGALNACT1 disturb glycosaminoglycan synthesis and cause a mild skeletal dysplasia with advanced bone age, CSGALNACT1-CDG.

20.
Genes (Basel) ; 11(1)2019 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-31877759

RESUMO

Variants in more than 271 different genes have been linked to hereditary retinal diseases, making comprehensive genomic approaches mandatory for accurate diagnosis. We explored the genetic landscape of retinal disorders in consanguineous families from North-Western Pakistan, harboring a population of approximately 35 million inhabitants that remains relatively isolated and highly inbred (~50% consanguinity). We leveraged on the high degree of consanguinity by applying genome-wide high-density single-nucleotide polymorphism (SNP) genotyping followed by targeted Sanger sequencing of candidate gene(s) lying inside autozygous intervals. In addition, we performed whole-exome sequencing (WES) on at least one proband per family. We identified 7 known and 4 novel variants in a total of 10 genes (ABCA4, BBS2, CNGA1, CNGA3, CNGB3, MKKS, NMNAT1, PDE6B, RPE65, and TULP1) previously known to cause inherited retinal diseases. In spite of all families being consanguineous, compound heterozygosity was detected in one family. All homozygous pathogenic variants resided in autozygous intervals ≥2.0 Mb in size. Putative founder variants were observed in the ABCA4 (NM_000350.2:c.214G>A; p.Gly72Arg; ten families) and NMNAT1 genes (NM_022787.3:c.25G>A; p.Val9Met; two families). We conclude that geographic isolation and sociocultural tradition of intrafamilial mating in North-Western Pakistan favor both the clinical manifestation of rare "generic" variants and the prevalence of founder mutations.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Mutação , Doenças Retinianas/genética , Sequenciamento Completo do Exoma/métodos , Consanguinidade , Análise Mutacional de DNA , Feminino , Efeito Fundador , Humanos , Masculino , Nicotinamida-Nucleotídeo Adenililtransferase/genética , Paquistão/epidemiologia , Linhagem , Prevalência , Doenças Retinianas/epidemiologia , Análise de Sequência de DNA
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