Genomica di nuova generazione e diagnosi prenatale

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1 Genomica di nuova generazione e diagnosi prenatale Negli ultimi anni, gli straordinari progressi conseguiti nel settore della genomica e delle biotecnologie hanno posto le basi per leggere e comprendere le informazioni contenute nel genoma fetale. In particolare le nuove tecnologie di sequenziamento, Next Generation Sequencing (NGS), ci permettono oggi di accedere alla sequenza del DNA in modo più facile ed efficace, fornendo una valutazione approfondita dell informazione genetica del feto. Il test PrenatalScreen PrenatalScreen è un test diagnostico, sviluppato da GENOMA Group, che permette di eseguire nel feto un analisi multipla di oltre malattie genetiche, tra cui quelle più frequenti nella popolazione italiana, come la Fibrosi Cistica, l Anemia Falciforme, la Talassemia, l Atrofia Muscolare Spinale, la Sordità Ereditaria. PrenatalScreen consente alla gestante di conoscere, attraverso l analisi del DNA fetale, se il bambino è affetto da gravi malattie genetiche. Finalità dell esame PrenatalScreen è viene eseguito su DNA estratto da cellule fetali presenti nel liquido amniotico, e prelevate mediante amniocentesi, oppure nei villi coriali, prelevate mediante villocentesi. La sua finalità è lo studio nel feto di malattie genetiche gravi, tra cui quelle più frequenti nella popolazione italiana. I geni elencati in Tabella 1, sono stati selezionati in base all incidenza nella popolazione delle malattie causate da mutazioni in tali geni, alla gravità del fenotipo clinico alla nascita ed all importanza del quadro patogenetico associato, seguendo le indicazioni dell American College of Medical Genetics (ACMG)(Grody et al., Genet Med 2013:15: ). Indicazioni al test PrenatalScreen PrenatalScreen è indicato nei seguenti casi: Anamnesi personale/familiare di malattie genetiche ereditarie; Per le gestanti che desiderano ridurre il rischio di una malattia genetica nel feto; Per gravidanze ottenute sia tramite concepimento naturale che mediante l accesso a tecniche di procreazione medicalmente assistita (PMA); Per le coppie che hanno fatto ricorso a tecniche di fecondazione eterologa. Come viene effettuato il test PrenatalScreen? Il test PrenatalScreen su liquido amniotico viene effettuato mediante il prelievo di ml di liquido amniotico per via trans-addominale, sotto controllo ecografico, tra la 15 e la 18 settimana di gestazione. Il liquido prelevato viene centrifugato per separare la parte liquida dalla frazione corpuscolata, costituita dalle cellule fetali che sono in sospensione nel liquido amniotico. Tali cellule, definite amniociti, sono sottoposte ad estrazione del DNA. Pag. 1 di 31

2 Il test PrenatalScreen su Villi Coriali viene effettuato mediante il prelievo di 20 mg circa di villi coriali per via trans-addominale sotto controllo ecografico, tra la 11 e la 13 settimana di gestazione. Il materiale prelevato viene prima lavato ed osservato al microscopio per separare il tessuto materno dal tessuto fetale, e successivamente sottoposto ad estrazione del DNA. Il DNA isolato dalle cellule fetali viene quindi amplificato mediante tecnica PCR.. Successivamente, attraverso un processo tecnologico avanzato di sequenziamento massivo parallelo (MPS), che impiega tecniche di Next Generation Sequencing (NGS) utilizzando sequenziatori ILLUMINA, si sequenziano completamente 744 geni (esoni e regioni introniche adiacenti, ± 5 nucleotidi)(tabella 1) ad elevata profondità di lettura. Le sequenze geniche ottenute vengono analizzate attraverso un avanzata analisi bioinformatica, per determinare la presenza di eventuali mutazioni nei geni in esame. Risultati ottenibili con il test PrenatalScreen POSITIVO Presenza di una o più mutazioni: indica che il test ha rilevato una o più mutazioni a livello di uno (o più) geni. Il nostro genetista, in sede di consulenza genetica, spiegherà in maniera dettagliata il significato del risultato del test ed, eventualmente, prospetterà la necessità di estendere l esame ai genitori, al fine di verificare la trasmissione ereditaria della variante riscontrata. Le mutazioni riscontrabili tramite il test PrenatalScreen possono rientrare nelle seguenti categorie prognostiche: o con significato patologico noto; o con significato benigno in quanto sono riscontrabili in individui normali e sono prive di significato patologico; o con significato incerto in quanto non ancora note o caratterizzate dalla comunità medicoscientifica. NEGATIVO - Assenza di mutazioni: indica che il test non ha rilevato la presenza di mutazioni nei geni esaminati. Tale risultato riduce notevolmente le possibilità che il feto abbia le malattie genetiche esaminate, ma non può garantire che il feto sia sano. Parametri utilizzati per la refertazione delle varianti genetiche L analisi è mirata esclusivamente ai geni elencati in Tabella 1. Verranno refertate solo le mutazioni classificate come a significato patogenetiche noto, sulla base dei dati della letteratura scientifica e la classificazione presente nel database di riferimento Human Gene Mutation Database (HGMD), aggiornato alla data del prelievo. Inoltre, seguendo le indicazioni dell American College of Medical Genetics (ACMG), sono state considerate come patogenetiche o presunte patogenetiche solo le mutazioni con un valore di Minor Allele Frequency (MAF) <5% (1000 Genomes Project), riferibile come la frequenza di ricorrenza dell allele meno comune all interno della popolazione. Target Coverage Si intende per Target Coverage, il numero medio di letture (reads) ottenute dal sequenziamento per ciascuna base nucleotidica costituente il gene. Le varianti con una profondità di lettura (numero di reads) inferiore a 30X non sono vengono evidenziate dall algoritmo di analisi bioinformatica. Pag. 2 di 31

3 Accuratezza del test PrenatalScreen Le tecniche attuali di sequenziamento del DNA producono risultati con un accuratezza superiore al 99%. Benché questo test sia molto accurato bisogna sempre considerare i limiti dell esame, di seguito descritti. Limiti del test PrenatalScreen Questo esame valuta solo le malattie genetiche ed i geni elencati in Tabella 1. Il test non evidenzia altre malattie genetiche o geni non specificamente investigati. L esame inoltre non è in grado di evidenziare: mutazioni localizzate nelle regioni introniche oltre ± 5 nucleotidi dai breakpoints; delezioni, inversioni o duplicazioni maggiori di 20 bp; mosaicismi della linea germinale (cioè mutazioni presenti solo nei gameti). Un risultato NEGATIVO - Assenza di mutazioni per i geni investigati non esclude la possibilità che nel feto siano presenti mutazioni localizzate in una regione del genoma non investigata dall esame. E possibile che alcune zone del proprio DNA non possano essere sequenziate o che abbiano una copertura inferiore ai limiti fissati dagli esperti di GENOMA Group per garantire un analisi accurata delle varianti. Queste regioni non saranno quindi comprese nell analisi qualora non superino gli standard qualitativi richiesti. In alcuni casi, il risultato di un analisi genomica può rivelare una variante o mutazione del DNA con un significato clinico non certo o non determinabile in base alle attuali conoscenze medicoscientifiche. Inoltre identificare una variante genetica non permette sempre di predire con certezza se e quando una persona svilupperà una certa patologia o la severità dei sintomi correlati. Il valore di alcune delle varianti riscontrate con il test può quindi non essere determinabile in base alle conoscenze mediche attuali. L interpretazione delle varianti genetiche si basa sulle più recenti conoscenze disponibili al momento dell analisi. Tale interpretazione potrebbe cambiare in futuro con l acquisizione di nuove informazioni scientifiche e mediche sulla struttura del genoma ed influire sulla valutazione stessa delle varianti. Alcune patologie possono essere causate o regolate da più di una variante nel suo DNA in uno o più geni. Alcune di queste varianti possono non essere ancora state identificate o validate dalla comunità scientifica e quindi non essere riportate come patogenetiche al momento dell analisi. Per un interpretazione corretta dei risultati è importante avere informazioni accurate circa lo stato di salute ed eventuali patologie nella storia clinica dell individuo e dei suoi familiari. Ciò permette una migliore interpretazione dei risultati genetici da parte dei nostri genetisti. Limite intrinseco della metodologia NGS utilizzata è la mancanza di uniformità di coverage per ciascuna regione genica analizzata. La qualità e la quantità del DNA ottenuto da campioni biologici prenatali è una delle possibili cause di tale mancanza di uniformità, potenzialmente responsabile della mancata identificazione di mutazioni geniche. Tale limite si traduce nella possibilità, insita nelle metodiche NGS, che specifiche mutazioni dei geni selezionati potrebbero non essere state rilevate dal test. Pag. 3 di 31

4 Tabella 1: PrenatalScreen - Elenco dei geni analizzati e della malattie genetiche investigate MALATTIA PhenoMIM GENE 1 17-alpha-hydroxylase/17,20-lyase deficiency CYP17A beta-hydroxysteroid dehydrogenase X deficiency HSD17B beta-hydroxysteroid dehydrogenase, type II, deficiency HSD3B2 4 3-hydroxy-3-methylglutaric aciduria HMGCL 5 3-methylglutaconic aciduria type AUH 6 3-methylglutaconic aciduria type OPA3 7 46XY sex reversal NR5A1 8 4-hydroxybutyric aciduria ALDH5A1 9 Aarskog-Scott syndrome FGD1 10 ABCD syndrome EDNRB 11 Acampomelic campomelic dysplasia SOX9 12 Achalasia-addisonianism-alacrimia syndrome AAAS 13 Achondrogenesis type 1B SLC26A2 14 Achondrogenesis, type IA TRIP11 15 Achondrogenesis, type II or hypochondrogenesis COL2A1 16 Achondroplasia FGFR3 17 Acromicric dysplasia FBN1 18 Acyl-CoA dehydrogenase 9 deficiency ACAD9 19 Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency CYP11B1 20 Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete CYP11A1 21 Adrenocortical insufficiency NR5A1 22 Adrenoleukodystrophy ABCD1 23 Adult neuronal ceroid lipofuscinosis PPT1 24 Adult neuronal ceroid lipofuscinosis CTSD 25 Adult neuronal ceroid lipofuscinosis 4A CLN6 26 Aicardi-Goutières syndrome TREX1 27 Aicardi-Goutieres syndrome RNASEH2B 28 Aicardi-Goutieres syndrome RNASEH2C 29 Aicardi-Goutieres syndrome RNASEH2A 30 Aicardi-Goutieres syndrome SAMHD1 31 Aicardi-Goutieres syndrome ADAR 32 Aldosteronism, glucocorticoid-remediable CYP11B1 33 Allan-Herndon-Dudley syndrome SLC16A2 34 Alpers syndrome POLG 35 Alpha-methylacyl-Coa Racemase deficiency AMACR 36 Alpha-thalassemia HBA1- HBA2 Pag. 4 di 31

5 37 Alpha-thalassemia myelodysplasia syndrome, somatic ATRX 38 Alpha-thalassemia/mental retardation syndrome ATRX 39 Alport syndrome X-Linked COL4A5 40 Alport syndrome autosomal recessive COL4A3 - COL4A4 41 Alström syndrome ALMS1 42 Amish infantile epilepsy syndrome ST3GAL5 43 Amyotrophic lateral sclerosis FIG4 44 Amyotrophic lateral sclerosis 2, juvenile ALS2 45 Anauxetic dysplasia RMRP 46 Andersen syndrome KCNJ2 47 Angelman syndrome UBE3A 48 Antenatal Bartter syndrome KCNJ1 49 Antenatal Bartter syndrome type SLC12A1 50 Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis POR 51 Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis FGFR2 52 Apert syndrome FGFR2 53 Aplasia/hypoplasia of limbs and pelvis WNT7A 54 Aplastic anemia NBN 55 Apparent mineralocorticoid excess HSD11B2 56 Argininosuccinic aciduria ASL 57 Aromatic L-amino acid decarboxylase deficiency DDC 58 Arrhythmogenic right ventricular dysplasia RYR2 59 Arthrogryposis - renal dysfunction - cholestasis VPS33B 60 Arthrogryposis multiplex congenita, distal, type TPM2 61 Arthrogryposis multiplex congenita, distal, type 2B TNNI2 62 Arthrogryposis, distal, type 2B TPM2 63 Arthrogryposis, renal dysfunction, and cholestasis VIPAR 64 Asperger syndrome susceptibility, X-linked NLGN3 65 Ataxia - oculomotor apraxia type APTX 66 Ataxia with vitamin E deficiency TTPA 67 Ataxia-telangiectasia ATM 68 Atelosteogenesis type II SLC26A2 69 Atrial fibrillation, familial, SCN3B 70 Atrial fibrillation, familial, SCN4B 71 Atrial fibrillation, familial, KCNQ1 72 Atrial fibrillation, familial, KCNE2 73 Atrial fibrillation, familial, KCNJ2 74 Autism, susceptibility to, X-linked RPL10 Pag. 5 di 31

6 75 Autoimmune lymphoproliferative syndrome type IV NRAS 76 Autoimmune lymphoproliferative syndrome, type IA FAS 77 Autoimmune lymphoproliferative syndrome, type IB FASLG 78 Autoimmune lymphoproliferative syndrome, type II CASP10 79 Autoimmune polyendocrinopathy syndrome, type I AIRE 80 Autosomal dominant Charcot-Marie-Tooth disease type 2K GDAP1 81 Autosomal recessive ataxia due to ubiquinone deficiency ADCK3 82 Autosomal recessive Charcot-Marie-Tooth disease with hoarseness GDAP1 83 Autosomal recessive distal spinal muscular atrophy type PLEKHG5 84 Autosomal recessive dopa-responsive dystonia TH 85 Autosomal recessive hypophosphatemic rickets DMP1 86 Autosomal recessive hypophosphatemic rickets ENPP1 87 Autosomal recessive intermediate Charcot-Marie-Tooth disease type A GDAP1 88 Autosomal recessive limb-girdle muscular dystrophy type 2I FKRP 89 Autosomal recessive limb-girdle muscular dystrophy type C POMT1 - POMGNT1 - POMT2 90 Autosomal recessive malignant osteopetrosis TCIRG1 91 Autosomal recessive malignant osteopetrosis CLCN7 92 Autosomal recessive nonsyndromic sensorineural deafness type DFNB CDH23 93 Autosomal recessive nonsyndromic sensorineural deafness type DFNB USH1C 94 Autosomal recessive nonsyndromic sensorineural deafness type DFNB1A GJB2 95 Autosomal recessive nonsyndromic sensorineural deafness type DFNB MYO7A 96 Autosomal recessive polycystic kidney disease PKHD1 97 Autosomal recessive progressive external ophthalmoplegia POLG 98 Autosomal recessive spastic ataxia of Charlevoix-Saguenay SACS 99 Autosomal recessive spondylocostal dysostosis DLL3 100 Avascular necrosis of the femoral head COL2A1 101 Bannayan-Riley-Ruvalcaba syndrome PTEN 102 Bardet-Biedl syndrome TRIM Basal cell carcinoma, somatic PTCH1 104 Basal cell nevus syndrome PTCH1 105 Beare-Stevenson cutis gyrata syndrome FGFR2 106 Becker muscular dystrophy DMD 107 Beckwith-Wiedemann syndrome CDKN1C - H19 - NSD1 108 Bent bone dysplasia syndrome FGFR2 109 Beta-thalassemia HBB 110 Bethlem myopathy COL6A1 - COL6A2 - COL6A3 Pag. 6 di 31

7 111 Bifunctional enzyme deficiency HSD17B4 112 Biotinidase deficiency BTD 113 Björnstad syndrome BCS1L 114 Bloom syndrome BLM 115 Borjeson-Forssman-Lehmann syndrome PHF6 116 Brachyolmia type TRPV4 117 Brachytelephalangic chondrodysplasia punctata ARSE 118 Brittle cornea syndrome ZNF Brugada syndrome GPD1L 120 Brugada syndrome SCN3B 121 Brunner syndrome MAOA 122 Buschke-Ollendorff syndrome LEMD3 123 Caffey disease COL1A1 124 Campomelic dysplasia with autosomal sex reversal SOX9 125 Canavan disease ASPA 126 CAP myopathy TPM3 127 CAP myopathy TPM2 128 Carbamoylphosphate synthetase deficiency CPS1 129 Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency SCO2 130 Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency COX Cardiofaciocutaneous syndrome BRAF 132 Cardiofaciocutaneous syndrome KRAS 133 Cardiofaciocutaneous syndrome MAP2K1 134 Cardiofaciocutaneous syndrome MAP2K2 135 Cardiomyopathy, familial hypertrophic CAV3 136 Carnitine deficiency, systemic primary SLC22A5 137 Carnitine palmitoyl transferase 1A deficiency CPT1A 138 Carnitine palmitoyl transferase II deficiency, infantile form CPT2 139 Carnitine palmitoyl transferase II deficiency, neonatal form CPT2 140 Carnitine-acylcarnitine translocase deficiency SLC25A Carpenter syndrome RAB Cartilage-hair hypoplasia RMRP 143 Cataract - intellectual deficit - hypogonadism RAB3GAP2 144 Cataract 40, X-linked NHS 145 CATSHL syndrome FGFR3 146 Central core disease RYR1 147 Central hypoventilation syndrome, congenital RET 148 Cerebellar ataxia - intellectual deficit - dysequilibrium syndrome VLDLR Pag. 7 di 31

8 149 Cerebral dysgenesis-neuropathy-ichthyosis-palmoplantar keratoderma syndrome SNAP Cerebrotendinous xanthomatosis CYP27A1 151 Charcot-Marie-Tooth disease axonal type 2B LMNA 152 Charcot-Marie-Tooth disease type 4A GDAP1 153 Charcot-Marie-Tooth disease type 4E EGR2 154 Charcot-Marie-Tooth disease type 4F PRX 155 Charcot-Marie-Tooth disease type 4H FGD4 156 Charcot-Marie-Tooth disease, axonal, type 2M DNM2 157 Charcot-Marie-Tooth disease, dominant intermediate B DNM2 158 Charcot-Marie-Tooth disease, type 1A PMP Charcot-Marie-Tooth disease, type 1B MPZ 160 Charcot-Marie-Tooth disease, type 1C LITAF 161 Charcot-Marie-Tooth disease, type 1E PMP Charcot-Marie-Tooth disease, type 1F NEFL 163 Charcot-Marie-Tooth disease, type 2A KIF1B 164 Charcot-Marie-Tooth disease, type 2A MFN2 165 Charcot-Marie-Tooth disease, type 2B RAB7A 166 Charcot-Marie-Tooth disease, type 2D GARS 167 Charcot-Marie-Tooth disease, type 2E NEFL 168 Charcot-Marie-Tooth disease, type 2I MPZ 169 Charcot-Marie-Tooth disease, type 2J MPZ 170 Charcot-Marie-Tooth disease, type 4B MTMR2 171 Charcot-Marie-Tooth disease, type 4B SBF2 172 Charcot-Marie-Tooth disease, type 4C SH3TC2 173 Charcot-Marie-Tooth disease, type 4D NDRG1 174 Charcot-Marie-Tooth disease, type 4J FIG4 175 Charcot-Marie-Tooth neuropathy, X-linked dominant, GJB1 176 CHARGE syndrome CHD7 177 Chediak-Higashi syndrome LYST 178 Chilblain lupus SAMHD1 179 CHILD syndrome NSDHL 180 Childhood-onset hypophosphatasia ALPL 181 Cholestasis, benign recurrent intrahepatic ATP8B1 182 Cholestasis, benign recurrent intrahepatic, ABCB Cholestasis, intrahepatic, of pregnancy, ATP8B1 184 Cholestasis, intrahepatic, of pregnancy, ABCB4 185 Cholestasis, progressive familial intrahepatic ATP8B1 186 Cholestasis, progressive familial intrahepatic ABCB Cholestasis, progressive familial intrahepatic ABCB4 Pag. 8 di 31

9 188 Chondrodysplasia, Blomstrand type PTH1R 189 Ciliary dyskinesia, primary, DNAI1 190 Ciliary dyskinesia, primary, DNAH5 191 Citrullinemia type I ASS1 192 CK syndrome NSDHL 193 Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency CYP21A2 194 Classic galactosemia GALT 195 Classic maple syrup urine disease DBT 196 Classical homocystinuria CBS 197 COACH syndrome TMEM Cockayne syndrome type A ERCC8 199 Cockayne syndrome type B ERCC6 200 Coenzyme Q10 deficiency, primary, COQ9 201 Coffin-Lowry syndrome RPS6KA3 202 COFS syndrome ERCC6 203 Cohen Syndrome type VPS13B 204 Combined immunodeficiency with skin granulomas RAG1 - RAG2 205 Combined oxidative phosphorylation defect type MRPS Combined oxidative phosphorylation defect type MRPS Combined oxidative phosphorylation deficiency TUFM 208 Combined pituitary hormone deficiencies, genetic forms HESX1 - PROP1 - POU1F1 209 Combined pituitary hormone deficiency with spine abnormalities LHX3 210 Complete androgen insensitivity syndrome AR 211 Complex I, mitochondrial respiratory chain, deficiency of NDUFS6 212 Congenital bile acid synthesis defect type AMACR 213 Congenital disorder of glycosylation type 1a PMM2 214 Congenital disorder of glycosylation type 1b MPI 215 Congenital disorder of glycosylation type 1e DPM1 216 Congenital disorder of glycosylation type 1j DPAGT1 217 Congenital disorder of glycosylation type 2a MGAT2 218 Congenital disorder of glycosylation type 2c SLC35C1 219 Congenital disorder of glycosylation type 2d B4GALT1 220 Congenital disorder of glycosylation type 2f SLC35A1 221 Congenital disorder of glycosylation type Ic ALG6 222 Congenital disorder of glycosylation type Ik ALG1 223 Congenital disorder of glycosylation, type Id ALG3 224 Congenital disorder of glycosylation, type If MPDU1 225 Congenital disorder of glycosylation, type Ig ALG12 Pag. 9 di 31

10 226 Congenital disorder of glycosylation, type Ih ALG8 227 Congenital disorder of glycosylation, type Ii ALG2 228 Congenital disorder of glycosylation, type IIb MOGS 229 Congenital disorder of glycosylation, type IIe COG7 230 Congenital disorder of glycosylation, type IIg COG1 231 Congenital disorder of glycosylation, type IIh COG8 232 Congenital disorder of glycosylation, type Il ALG9 233 Congenital disorder of glycosylation, type Im DOLK 234 Congenital disorder of glycosylation, type In RFT1 235 Congenital disorder of glycosylation, type Iq SRD5A3 236 Congenital fibrinogen deficiency FGA 237 Congenital heart defects, nonsyndromic, 1, X-linked ZIC3 238 Congenital hereditary endothelial dystrophy type II SLC4A Congenital lipoid adrenal hyperplasia STAR 240 Congenital malabsorptive diarrhea due to paucity of enteroendocrine cells NEUROG3 241 Congenital muscular dystrophy type 1A LAMA2 242 Congenital muscular dystrophy type 1D LARGE 243 Congenital muscular dystrophy type 5B FKRP 244 Congenital muscular dystrophy with cerebellar involvement POMGNT1 - POMT1 - POMT2 245 Congenital myopathy with excess of muscle spindles HRAS 246 Corneal dystrophy - perceptive deafness SLC4A Cornelia de Lange syndrome NIPBL 248 Cornelia de Lange syndrome SMC1A 249 Cornelia de Lange syndrome SMC3 250 Corpus callosum agenesis - neuronopathy SLC12A6 Corpus callosum hypoplasia-retardation-adducted thumbs-spasticityhydrocephalus syndrome L1CAM 252 Corpus callosum, agenesis of, with mental retardation IGBP1 253 Costello syndrome HRAS 254 Cowden syndrome PTEN 255 Craniofacial-deafness-hand syndrome PAX3 256 Craniofacial-skeletal-dermatologic dysplasia FGFR2 257 Craniofrontonasal dysplasia EFNB1 258 Craniosynostosis, type TWIST1 259 Creatine phosphokinase, elevated serum CAV3 260 Crouzon syndrome FGFR2 261 Crouzon syndrome with acanthosis nigricans FGFR3 262 Culler-Jones syndrome GLI2 Pag. 10 di 31

11 263 Cutis laxa, autosomal dominant FBLN5 264 Cutis laxa, autosomal recessive, type IA FBLN5 265 Cutis laxa, autosomal recessive, type IB EFEMP2 266 Cutis laxa, autosomal recessive, type IIA ATP6V0A2 267 Cystic fibrosis; mucoviscidosis CFTR 268 Cystinosis CTNS 269 Czech dysplasia COL2A1 270 Danon disease LAMP2 271 Deafness - encephaloneuropathy - obesity - valvulopathy PDSS1 272 Deafness, autosomal dominant COL11A2 273 Deafness, autosomal dominant 3B GJB6 274 Deafness, autosomal dominant type DIAPH1 275 Deafness, autosomal dominant type EYA4 276 Deafness, autosomal dominant type TECTA 277 Deafness, autosomal dominant type POU4F3 278 Deafness, autosomal dominant type MYH9 279 Deafness, autosomal dominant type ACTG1 280 Deafness, autosomal dominant type MYO6 281 Deafness, autosomal dominant type SIX1 282 Deafness, autosomal dominant type SLC17A8 283 Deafness, autosomal dominant type GRHL2 284 Deafness, autosomal dominant type 2A KCNQ4 285 Deafness, autosomal dominant type 2B GJB3 286 Deafness, autosomal dominant type TMC1 287 Deafness, autosomal dominant type MYH Deafness, autosomal dominant type CRYM 289 Deafness, autosomal dominant type MYO1A 290 Deafness, autosomal dominant type DFNA5 291 Deafness, autosomal dominant type MIR Deafness, autosomal dominant type WFS1 293 Deafness, autosomal dominant type DIABLO 294 Deafness, autosomal dominant type COCH 295 Deafness, autosomal recessive 1B GJB6 296 Deafness, autosomal recessive COL11A2 297 Deafness, digenic GJB2/GJB GJB6 298 Dejerine-Sottas disease MPZ - PMP Dent disease CLCN5 300 Dent disease OCRL 301 Denys-Drash syndrome WT1 Pag. 11 di 31

12 302 Dermatopathia pigmentosa reticularis KRT Desmosterolosis DHCR Diabetes mellitus, noninsulin-dependent ABCC8 305 Diabetes mellitus, permanent neonatal ABCC8 306 Diabetes mellitus, transient neonatal ABCC8 307 Diastrophic dwarfism SLC26A2 308 Digital arthropathy-brachydactyly, familial TRPV4 309 Dihydropyrimidine dehydrogenase deficiency DPYD 310 Dilated cardiomyopathy with ataxia DNAJC Donnai-Barrow syndrome LRP2 312 Dowling-Degos disease KRT5 313 Duchenne muscular dystrophy DMD 314 Dyschromatosis symmetrica hereditaria ADAR 315 Dyskeratosis congenita X-linked DKC1 316 Dystonia-1, torsion TOR1A 317 Dystonia-11, myoclonic SGCE 318 Dystrophic epidermolysis bullosa pruriginosa COL7A ARX Early infantile epileptic encephalopathy SLC25A Ectodermal dysplasia 1, hypohidrotic, X-linked EDA 321 Ectodermal dysplasia 2, Clouston type GJB6 322 Ectodermal dysplasia, hypohidrotic, with immune deficiency IKBKG 323 Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency IKBKG 324 Ectopia lentis, familial FBN1 325 Ehlers-Danlos syndrome type PLOD1 326 Ehlers-Danlos syndrome, cardiac valvular type COL1A2 327 Ehlers-Danlos syndrome, type I COL5A1 - COL5A2 - COL1A1 328 Ehlers-Danlos syndrome, type II COL5A1 329 Ehlers-Danlos syndrome, type III COL3A1 330 Ehlers-Danlos syndrome, type IV COL3A1 331 Ehlers-Danlos syndrome, type VIIA COL1A1 332 Eiken syndrome PTH1R 333 Elliptocytosis EPB Ellis-van Creveld syndrome EVC2 335 Emery-Dreifuss muscular dystrophy 1, X-linked EMD 336 Encephalopathy due to prosaposin deficiency PSAP 337 Encephalopathy, progressive, with or without lipodystrophy BSCL2 338 Epidermolysis bullosa simplex with muscular dystrophy PLEC Pag. 12 di 31

13 339 Epidermolysis bullosa simplex with pyloric atresia PLEC 340 Epidermolysis bullosa simplex, Dowling-Meara type KRT14 - KRT5 341 Epidermolysis bullosa simplex, Koebner type KRT14 - KRT5 342 Epidermolysis bullosa simplex, recessive KRT14 - KRT5 343 Epidermolysis bullosa simplex, Weber-Cockayne type KRT14 - KRT5 344 Epidermolysis bullosa simplex-mp KRT5 345 Epidermylysis bullosa simplex-mcr KRT5 346 Epilepsy, familial temporal lobe, LGI1 347 Epilepsy, progressive myoclonic 2A (Lafora) EPM2A 348 Epilepsy, progressive myoclonic 2B (Lafora) NHLRC1 349 Epilepsy, pyridoxine-dependent ALDH7A1 350 Epilepsy, X-linked, with variable learning disabilities and behavior disorders SYN1 351 Epileptic encephalopathy, early infantile, ST3GAL3 352 Epileptic encephalopathy, early infantile, CDKL5 353 Epileptic encephalopathy, early infantile, ARHGEF9 354 Epileptic encephalopathy, early infantile, PCDH Epiphyseal dysplasia, multiple COMP 356 Epiphyseal dysplasia, multiple, with myopia and deafness COL2A1 357 Erythrocytosis, familial, VHL 358 Escobar syndrome CHRNG 359 Ethylmalonic encephalopathy ETHE1 360 Exostoses, multiple, type EXT1 361 Exostoses, multiple, type EXT2 362 Exudative vitreoretinopathy 2, X-linked NDP 363 Fabry disease GLA 364 Failure of tooth eruption, primary PTH1R 365 Familial dysautonomia IKBKAP 366 Familial hypomagnesemia - hypercalciuria - nephrocalcinosis - severe ocular CLDN Familial Mediterranean fever MEFV 368 Fanconi anemia complementation group C FANCC 369 Fanconi anemia, complementation group A FANCA 370 Fanconi anemia, complementation group B FANCB 371 Fanconi anemia, complementation group G FANCG 372 Fatal infantile lactic acidosis with methylmalonic aciduria SUCLG1 Fatal mitochondrial disease due to combined oxidative phosphorylation TSFM deficiency Favism G6PD 375 Fertile eunuch syndrome GNRHR Pag. 13 di 31

14 376 Fetal akinesia deformation sequence RAPSN DOK7 377 Fetal Gaucher disease GBA 378 FG syndrome CASK 379 Fibrochondrogenesis COL11A1 380 Fibrochondrogenesis COL11A2 381 Fibromatosis, gingival SOS1 382 Fibular hypoplasia or aplasia - femoral bowing - oligodactyly WNT7A 383 Focal cortical dysplasia, Taylor balloon cell type TSC1 384 Focal dermal hypoplasia PORCN 385 Fraser syndrome (gene FRAS1) FRAS1 - FREM2 386 Frasier syndrome WT1 387 Free sialic acid storage disease, infantile form SLC17A5 388 French-Canadian type Leigh syndrome LRPPRC 389 Fucosidosis FUCA1 390 Fumaric aciduria FH 391 Galactokinase deficiency with cataracts GALK1 392 Gallbladder disease ABCB4 393 Gaucher disease type GBA 394 Gaucher disease type GBA 395 Gaucher disease type 3C GBA 396 Geleophysic dysplasia ADAMTSL2 397 Geleophysic dysplasia FBN1 398 Generalized junctional epidermolysis bullosa, non-herlitz type COL17A1 399 Glutaric acidemia type ETFA - ETFB - ETFDH 400 Glutaryl-CoA dehydrogenase deficiency GCDH 401 Glutathione synthetase deficiency with 5-oxoprolinuria GSS 402 Glycerol kinase deficiency GK 403 Glycine encephalopathy AMT - GCSH - GLDC 404 Glycogen storage disease due to acid maltase deficiency GAA 405 Glycogen storage disease due to glucose-6-phosphatase deficiency type 1a G6PC 406 Glycogen storage disease due to glucose-6-phosphatase deficiency type b SLC37A4 407 Glycogen storage disease due to glucose-6-phosphatase deficiency type c SLC37A4 Glycogen storage disease due to glycogen branching enzyme deficiency, GBE1 childhood combined hepatic and myopathic form 409 Glycogen storage disease due to glycogen debranching enzyme deficiency AGL 410 Glycogen storage disease due to muscle glycogen phosphorylase deficiency PYGM 411 GM1 gangliosidosis type GLB1 412 GM1 gangliosidosis type GLB1 Pag. 14 di 31

15 413 GM1 gangliosidosis type GLB1 414 Gnathodiaphyseal dysplasia ANO5 415 GRACILE syndrome BCS1L 416 Greenberg dysplasia LBR 417 Griscelli disease type MYO5A 418 Griscelli disease type RAB27A 419 Guanidinoacetate methyltransferase deficiency GAMT 420 Heinz body anemia HBA2 421 Hemochromatosis HFE 422 Hemochromatosis, type 2A HFE2 423 Hemoglobin H disease, nondeletional HBA2 424 Hemolytic anemia due to G6PD deficiency G6PD 425 Hemolytic anemia due to red cell pyruvate kinase deficiency PKLR 426 Hemophagocytic lymphohistiocytosis, familial, PRF1 427 Hemophagocytic lymphohistiocytosis, familial, UNC13D 428 Hemophagocytic lymphohistiocytosis, familial, STX Hemophagocytic lymphohistiocytosis, familial, STXBP2 430 Hemophilia A F8 431 Hemophilia B F9 432 Hepatic venoocclusive disease with immunodeficiency SP Hepatoencephalopathy due to combined oxidative phosphorylation deficiency type GFM1 434 Hereditary fructose intolerance ALDOB 435 Hereditary motor and sensory neuropathy VI MFN2 436 Hereditary motor and sensory neuropathy, type IIc TRPV4 437 Hereditary sensory and autonomic neuropathy type NTRK1 438 Hermansky-Pudlak syndrome AP3B1 439 Hermansky-pudlak syndrome PLDN 440 Heterotaxy, visceral, 1, X-linked ZIC3 441 Heterotopia, periventricular FLNA 442 Histidinemia HAMP 443 Holocarboxylase synthetase deficiency HLCS 444 Holoprosencephaly DISP1 445 Holoprosencephaly SIX3 446 Holoprosencephaly SHH 447 Holoprosencephaly ZIC2 448 Holoprosencephaly PTCH1 449 Holoprosencephaly GLI2 450 Homocystinuria due to MTHFR deficienc MTHFR 451 Hoyeraal-Hreidarsson syndrome DKC1 Pag. 15 di 31

16 452 Hyaline fibromatosis syndrome ANTXR2 453 Hyperammonemia due to N-acetylglutamate synthetase deficiency NAGS 454 Hyper-IgE recurrent infection syndrome, autosomal recessive DOCK8 455 Hyperinsulinemic hypoglycemia, familial, ABCC8 456 Hyperornithinemia-hyperammonemia-homocitrullinuria SLC25A Hyperthyroidism, nonautoimmune TSHR 458 Hypochondroplasia FGFR3 459 Hypoglycemia of infancy, leucine-sensitive ABCC8 460 Hypogonadotropic hypogonadism CHD7 461 Hypogonadotropic hypogonadism 7 without anosmia GNRHR 462 Hypomyelination - congenital cataract FAM126A 463 Hypoparathyroidism - intellectual deficit - dysmorphism syndrome TBCE 464 Hypophosphatemic rickets CLCN5 465 Hypothyroidism, congenital, due to thyroid dysgenesis or hypoplasia PAX8 466 Hypothyroidism, congenital, nongoitrous, TSHR 467 Ichthyosis follicularis - alopecia - photophobia MBTPS2 468 Ichthyosis, autosomal recessive 4B (harlequin) ABCA Ichthyosis, congenital, autosomal recessive TGM1 470 Ichthyosis, congenital, autosomal recessive 4A ABCA Ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis CLDN1 472 IMAGE syndrome CDKN1C 473 Immunodeficiency STIM1 474 Immunodeficiency 17, CD3 gamma deficient CD3G 475 Immunodeficiency 18, SCID variant CD3E 476 Immunodeficiency CD3D 477 Immunodeficiency 27A, mycobacteriosis, AR IFNGR1 478 Immunodeficiency 28, mycobacteriosis IFNGR2 479 Immunodeficiency 29, mycobacteriosis IL12B 480 Immunodeficiency IL12RB1 481 Immunodeficiency 31A, mycobacteriosis, autosomal dominant STAT1 482 Immunodeficiency 31B, mycobacterial and viral infections, autosomal recessive STAT1 483 Immunodeficiency 31C, autosomal dominant STAT1 484 Immunodeficiency IKBKG 485 Immunodeficiency TYK2 486 Immunodeficiency ORAI1 487 Immunodeficiency, common variable, ICOS 488 Immunodeficiency, common variable, CD Immunodeficiency, X-linked MAGT1 490 Immunodeficiency-centromeric instability-facial anomalies syndrome DNMT3B Pag. 16 di 31

17 491 Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked FOXP3 492 Incontinentia pigmenti, type II IKBKG 493 Infantile bilateral striatal necrosis NUP Infantile hypophosphatasia ALPL 495 Infantile neuroaxonal dystrophy 2A PLA2G6 496 Infantile neuroaxonal dystrophy 2B PLA2G6 497 Infantile onset spinocerebellar ataxia C10orf2 498 Interleukin 1 receptor antagonist deficiency IL1RN 499 Isolated CoQ-cytochrome C reductase deficiency BCS1L 500 Isolated growth hormone deficiency type III BTK 501 Isolated thyroid-stimulating hormone deficiency TSHB 502 Isovaleric acidemia IVD 503 Jackson-Weiss syndrome FGFR2 504 Jervell and Lange-Nielsen syndrome KCNQ1 505 Jervell and Lange-Nielsen syndrome KCNE1 506 Jeune syndrome IFT Johanson-Blizzard syndrome UBR1 508 Joubert syndrome NPHP1 509 Joubert syndrome TMEM Joubert syndrome with hepatic defect RPGRIP1L 511 Joubert syndrome with ocular defect AHI1 512 Joubert syndrome with oculorenal defect CEP Junctional epidermolysis bullosa - pyloric atresia ITGA6 - ITGB4 514 Junctional epidermolysis bullosa, Herlitz type LAMA3- LAMB3 - LAMC2 515 Junctional epidermolysis bullosa, non-herlitz type ITGB4 - LAMA3- LAMB3- LAMC2 516 Juvenile neuronal ceroid lipofuscinosis CLN3 517 Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome SMAD4 518 Kabuki syndrome KMT2D (MLL2) 519 Kabuki syndrome KDM6A 520 Kahrizi syndrome SRD5A3 521 Kelley-Seegmiller syndrome HPRT1 522 Ketoacidosis due to beta-ketothiolase deficiency ACAT1 523 King-Denborough syndrome RYR1 524 Kniest dysplasia COL2A1 525 Krabbe disease GALC - PSAP Pag. 17 di 31

18 Lacticacidemia due to PDX1 deficiency PDHX 527 LADD syndrome FGFR2 - FGFR3 528 Late infantile neuronal ceroid lipofuscinosis MFSD8 529 Late infantile neuronal ceroid lipofuscinosis CLN5 530 Late infantile neuronal ceroid lipofuscinosis CLN6 531 Late infantile neuronal ceroid lipofuscinosis CLN8 532 Lathosterolosis SC5DL 533 Legg-Calve-Perthes disease COL2A1 534 Leigh syndrome BCS1L - DLD - NDUFAF2 - NDUFS4 - NDUFS7 - NDUFS3 - NDUFS8 535 Leigh syndrome due to cytochrome c oxidase deficiency COX Leigh syndrome due to mitochondrial COX4 deficiency COX COQ2-537 Leigh syndrome with nephrotic syndrome PDSS2 538 Leigh syndrome, due to COX deficiency SURF1 539 Leigh syndrome, X-linked PDHA1 540 LEOPARD syndrome PTPN LEOPARD syndrome RAF1 542 LEOPARD syndrome BRAF 543 Leprechaunism INSR 544 Lesch-Nyhan syndrome HPRT1 545 Lethal acantholytic epidermolysis bullosa DSP 546 Lethal ataxia with deafness and optic atrophy PRPS1 547 Lethal congenital contractural syndrome ERBB3 548 Lethal congenital contracture syndrome DNM2 549 Lethal congenital contracture syndrome type GLE1 550 Lethal osteosclerotic bone dysplasia FAM20C 551 Lethal restrictive dermopathy LMNA - ZMPSTE Leukemia, juvenile myelomonocytic PTPN Leukocyte adhesion deficiency, type III FERMT3 554 Leydig cell adenoma, somatic, with precocious puberty LHCGR 555 Leydig cell hypoplasia with hypergonadotropic hypogonadism LHCGR 556 Leydig cell hypoplasia with pseudohermaphroditism LHCGR 557 Lhermitte-Duclos syndrome PTEN 558 Limb girdle dystrophy with epidermolysis bullosa simplex PLEC Pag. 18 di 31

19 559 Lipodystrophy, congenital generalized, type BSCL2 560 Lissencephaly TUBA1A 561 Lissencephaly syndrome, Norman-Roberts type RELN 562 Lissencephaly, X-linked DCX 563 Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency HADH 564 Long QT syndrome KCNQ1 565 Long QT syndrome SNTA1 566 Long QT syndrome KCNH2 567 Long QT syndrome ANK2 568 Long QT syndrome KCNE1 569 Long QT syndrome KCNE2 570 Long QT syndrome CAV3 571 Long QT syndrome SCN4B 572 Long QT syndrome AKAP9 573 Luteinizing hormone resistance, female LHCGR 574 Lymphangioleiomyomatosis TSC1 575 Lymphoproliferative syndrome, X-linked, XIAP 576 Macrocephaly/autism syndrome PTEN 577 Macroglobulinemia, Waldenstrom MYD Macular degeneration, age-related, FBLN5 579 Mandibuloacral dysplasia with type A lipodystrophy LMNA 580 Mandibuloacral dysplasia with type B lipodystrophy ZMPSTE Mannosidosis, alpha-, types I and II MAN2B1 582 Maple syrup urine disease DLD - BCKDHA - BCKDHB 583 Marfan syndrome FBN1 584 Marinesco-Sjögren syndrome SIL1 585 Marshall syndrome COL11A1 586 Masa syndrome L1CAM 587 MASS syndrome FBN1 588 Meacham syndrome WT1 589 Meckel syndrome type MKS1 590 Meckel syndrome, type RPGRIP1L 591 Medium chain acyl-coa dehydrogenase deficiency ACADM 592 Medullary thyroid carcinoma RET 593 Megalencephalic leukoencephalopathy with subcortical cysts MLC1 594 Melorheostosis with osteopoikilosis LEMD3 595 Menkes disease ATP7A 596 Mental retardation and microcephaly and cerebellar hypoplasia CASK Pag. 19 di 31

20 597 Mental retardation syndrome, X-linked, Siderius type PHF8 598 Mental retardation, autosomal dominant type MBD5 599 Mental retardation, autosomal dominant type ARID1B 600 Mental retardation, autosomal dominant type ARID1A 601 Mental retardation, autosomal dominant type SMARCB1 602 Mental retardation, autosomal dominant type SMARCA4 603 Mental retardation, autosomal dominant type MEF2C 604 Mental retardation, autosomal dominant type SYNGAP1 605 Mental retardation, autosomal dominant type GRIN2B 606 Mental retardation, autosomal dominant type KIF1A 607 Mental retardation, autosomal recessive PRSS Mental retardation, autosomal recessive ST3GAL3 609 Mental retardation, autosomal recessive TRAPPC9 610 Mental retardation, autosomal recessive NSUN2 611 Mental retardation, autosomal recessive TUSC3 612 Mental retardation, autosomal recessive, GRIK2 613 Mental retardation, with or without nystagmus CASK 614 Mental retardation, X-linked AGTR2 615 Mental retardation, X-linked ELK1 616 Mental retardation, X-linked NLGN4X 617 Mental retardation, X-linked RPS6KA3 618 Mental retardation, X-linked 21/ IL1RAPL1 619 Mental retardation, X-linked 30/ PAK3 620 Mental retardation, X-linked GDI1 621 Mental retardation, X-linked ZNF Mental retardation, X-linked ARHGEF6 623 Mental retardation, X-linked TSPAN7 624 Mental retardation, X-linked ACSL4 625 Mental retardation, X-linked RAB39B 626 Mental retardation, X-linked FTSJ1 627 Mental retardation, X-linked ZDHHC Mental retardation, X-linked BRWD3 629 Mental retardation, X-linked GRIA3 630 Mental retardation, X-linked SYP 631 Mental retardation, X-linked ZNF Mental retardation, X-linked KIAA Mental retardation, X-linked syndromic FGD1 634 Mental retardation, X-linked syndromic AP1S2 635 Mental retardation, X-linked syndromic, Christianson type SLC9A6 Pag. 20 di 31