SUPPLEMENTARY INFORMATION

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1 Supplementary table 1. Inherited kinasopathies and their germline kinase mutation according to organ system involvement System-based disorders Disease name MOI Disease OMIM Gene name Symbol Locus Gene OMIM Total no. of mutations Type of mutation No. of mutations Domains carrying mutations or result of mutation Neurological Neuroblastoma AD ANAPLASTIC LYMPHOMA ALK 2p Missense 4 catalytic KINASE Early infantile epileptic encephalopathy type 2 XL CYCLIN-DEPENDENT KINASE- LIKE 5 CDKL5 Xp Missense in the catalytic, 3 in non-catalytic Termination 3 at exon 18 signal peptidase I serine active site truncated Aberrant splicing 2 IVS6 and IVS13 Deletion 1 N terminal and at catalytic Lethal congenital contractural syndrome type 2 AR V-ERB-B2 AVIAN ERYTHROBLASTIC LEUKEMIA ERBB3 12q Insertion 1 8 bp intronic insertion leading to premature truncation VIRAL ONCOGENE HOMOLOG 3 Epileptic encephalopathy, Lennox-Gaustaut type AR MITOGEN-ACTIVATED PROTEIN KINASE 10 MAPK10 4q Deletion 1 exon due to the balanced translocation t(y;4)(q11.2;q21) Myasthenic syndrome AR MUSCLE, SKELETAL, RECEPTOR MUSK 9q31.3-q Missense 1 catalytic TYROSINE KINASE Insertion 1 intronic leading to premature truncation Congenital insensitivity to AR NEUROTROPHIC TYROSINE NTRK1 1q21-q Missense 16 catalytic pain with anhidrosis KINASE, RECEPTOR, TYPE 1 Aberrant splicing 1 in IVS Insertion 1 nonsense Deletion 2 1 premature truncation, 1 in IVS4 Termination 1 1 at N terminal Pantothenate kinase-associated neurodegeneration AR PANTOTHENATE KINASE 2 PANK2 20p13-p Missense in the fumble (catalytic), 2 in transmembrane, rest prefumble Termination 2 pre-fumble Deletion 3 fumble (catalytic) Early-onset Parkinson disease 6 AR PTEN-INDUCED PUTATIVE KINASE 1 PINK1 1p Missense 15 9 in catalytic, rest precatalytic Termination 3 catalytic Ins/del 3 1 insertion at catalytic and 1 insertion leading to termination at C, one deletion of exons 6-8 Spinocerebellar ataxia type 14 AD PROTEIN KINASE C, GAMMA PRKCG 19q Missense 8 7 at the phorbol esters/diacylglycerol binding (C1 ), 1 in the C of the catalytic

2 Skeletal and craniosynostosis Amyotrophic lateral sclerosis-parkinsonism/dementia complex 1 ND TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY M, MEMBER 7 TRPM7 15q Missense 1 non-catalytic (cytoplasmic) Fibrodysplasia ossificans AD ACTIVIN A RECEPTOR, TYPE I ACVR1 2q23-q Missense 9 3 in TGF-beta type I GS-motif, rest progressiva in catalytic Deletion 1 deletion of aa 198 (TGF-beta type I GS-motif) Brachydactyly, type 2A AD BONE MORPHOGENETIC BMPR1B 4q23-q Missense 3 1 in TGF-beta type I GS-motif, 2 in PROTEIN RECEPTOR, TYPE IB catalytic Craniofrontonasal syndrome XL EPHRIN B1 EFNB1 Xq Missense 20 In extracellular Deletion 3 In extracellular Osteoglophonic dysplasia AD FIBROBLAST GROWTH FACTOR FGFR1 8p11.2-p Missense 5 1 in Ig-like #3, 2 3 Ig-like RECEPTOR 1 # 3, 2 in transmembrane Pfeiffer syndrome AD FIBROBLAST GROWTH FACTOR FGFR1 8p11.2-p Missense 1 between the 2nd and 3rd Ig-like RECEPTOR 1 Apert Syndrome AD FIBROBLAST GROWTH FACTOR FGFR2 10q Missense 2 between the 2nd and 3rd Ig-like RECEPTOR 2 Insertion 1 Alu-element upstream or within exon 9 Crouzon syndrome AD FIBROBLAST GROWTH FACTOR FGFR2 10q Missense to Ig-like #2, 1 3 to RECEPTOR 2 Ig-like #2, 30 in Ig-like #2, 4 in catalytic Deletion 2 Ig-like #2 Insertion 1 Ig-like #2 Lacrimoauriculodentodigital AD FIBROBLAST GROWTH FACTOR FGFR2 10q Missense 2 catalytic syndrome RECEPTOR 2 Deletion 1 catalytic Pfeiffer syndrome AD FIBROBLAST GROWTH FACTOR RECEPTOR 2 FGFR2 10q Missense 21 1 in Ig-like #1, 1 5 to Ig-like #2, 4 in catalytic core, remainder (15) in Ig-like #2 Aberrant splicing 2 2 at 5 -terminus Ins/Del 2 1 complex in-del at 5 -terminus, 1 deletion of residue 273 (Asp) in Ig-like #2 Achondrodysplasia AD FIBROBLAST GROWTH FACTOR RECEPTOR 3 FGFR3 4p Missense 7 1 in Ig-like #2, 5 5 to catalytic, 1 catalytic Muenke syndrome AD FIBROBLAST GROWTH FACTOR FGFR3 4p Missense 1 1 Ig-like #2 RECEPTOR 3 Thanatophoric dysplasia type 1 AD FIBROBLAST GROWTH FACTOR RECEPTOR 3 FGFR3 4p Missense 7 2 in catalytic, 3 in the extracellular region, 2 after Ig-like #3 Longer protein 3 stop codon mutated to an aminoacid codon

3 Hematological and vascular Thanatophoric dysplasia AD FIBROBLAST GROWTH FACTOR FGFR3 4p Missense 2 Ig-like #2 type 2 RECEPTOR 3 Robinow syndrome AR RECEPTOR TYROSINE KINASE- LIKE ORPHAN RECEPTOR 2 ROR2 9q Missense 5 1 in Ig-like C2-type, 1 in frizzled cysteine-rich, 2 in catalytic Termination 4 within exon 9 (catalytic ) Deletion 2 within exon 9 (in the catalytic ), exon 6 and 7 (in catalytic ) Hereditary hemorrhagic AD ACTIVIN A RECEPTOR, TYPE ACVRL1 12q Missense 42 8 in the activin receptor, 1 telangiectasia type 2 II-LIKE KINASE 1 close to the TM, 1 in the TGF-beta GS-motif, 35 in the catalytic Deletion 5 catalytic Frameshift 1 insertion of 51 new codons Primary pulmonary hypertension AD BONE MORPHOGENETIC BMPR2 2q Missense 16 6 in activin receptor, 6 1 PROTEIN RECEPTOR, TYPE II in catalytic, rest in non- catalytic regions Frameshift 4 premature truncation at: exon 12, transmembrane, c.230, c.368 Termination 8 2 in activin receptor, 1 in transmembrane, 3 in catalytic, 2 in N terminal Deletion 3 from exons 1-13, exon 2 and exon 10 Hereditary lymphedema AD FMS-LIKE TYROSINE KINASE 4 FLT4 5q Missense 10 1 in ATP-binding, rest in type 1A catalytic Deletion 1 catalytic Piebaldism AD V-KIT HARDY-ZUCKERMAN KIT 4q Missense 11 catalytic 4 FELINE SARCOMA VIRAL ONCOGENE HOMOLOG Ins/del 5 1 deletion of entire protein, 2 deletions and 1 duplication resulting in truncation before catalytic, 2 amino acids deleted in the catalytic Cutaneous and mucosal venous AD TEK TYROSINE KINASE, TEK 9p Missense 2 catalytic malformations ENDOTHELIAL Loeys-Dietz Syndrome (Type AD TRANSFORMING GROWTH TGFBR1 9q Missense 5 catalytic 1A) FACTOR-BETA RECEPTOR, TYPE I

4 Loeys-Dietz Syndrome (Type 2A) AD TRANSFORMING GROWTH FACTOR-BETA RECEPTOR, TYPE I Loeys-Dietz Syndrome AD TRANSFORMING GROWTH (Type 1B) FACTOR-BETA RECEPTOR, TYPE II Loeys-Dietz Syndrome AD TRANSFORMING GROWTH (Type 2B) FACTOR-BETA RECEPTOR, TYPE II Immunological Agammaglobulinemia XL BRUTON AGAMMAGLOBULINEMIA TYROSINE KINASE Hypohidrotic ectodermal XL INHIBITOR OF KAPPA LIGHT dysplasia with immune POLYPEPTIDE GENE ENHANCER deficiency (B CELL) KINASE Incontinentia pigmenti type 2 XL INHIBITOR OF KAPPA LIGHT POLYPEPTIDE GENE ENHANCER (B CELL) KINASE TGFBR1 9q Missense 4 1 in the transforming growth factor beta type I GS-motif, rest in catalytic TGFBR2 3p Missense 5 catalytic Termination 1 catalytic Aberrant splicing 3 TBR2 ecto TGFBR2 3p Missense 7 catalytic Aberrant splicing 1 catalytic BTK Xq21.3-q Missense in the pleckstrin homology (PH), 3 in Zinc-binding motif, 3 after the zinc-binding motif, 14 in SH3, 6 in the SH2 and 68 in catalytic Termination 11 2 in the PH, 3 in SH3, 1 in the SH2, 5 in catalytic. Aberrant splicing 6 leading to truncations at: C terminal end, SH3, SH2, catalytic ; skipping of exon 5; 1 at IVS-1 Insertions 7 C -terminal, PH, Btktype zinc finger, N -terminal, SH1, SH2, SH3. Deletions 10 2 in PH, translation start site, 2 in SH3, 2 in SH2, 2 in catalytic and exons IKBKG Xq Missense 9 5 in CYLD-interactiong, 1 in self-association region, 2 5 of CYLD-interacting Insertion 3 Duplication in coiled-coil, leads to truncation at N -terminus and coiled-coil Termination 2 1 in zinc-finger, 1 in CYLDinteracting IKBKG Xq Missense 5 2 in IKBKB-interacting, 1 in leucine-zipper, 1 in CYLDinteracting and 1 in selfassociation

5 Endocrine/ metabolic Ins/del 3 deletion at the 90th nucleotide and exon 4-10, insertion in self-association Termination 1 pre-ikbkb-interacting Duplication 2 1 in pre-ikbkb-interacting, 1 in CYLD-interacting Invasive pneumococcal AR INTERLEUKIN 1 RECEPTOR- IRAK4 12q Aberrant splicing 2 in IVS10 disease ASSOCIATED KINASE 4 Pyogenic bacterial infections AR INTERLEUKIN 1 RECEPTOR- IRAK4 12q Deletion 2 both in catalytic ASSOCIATED KINASE 4 Termination 1 catalytic Severe-combined immunodeficiency (selective T-cell AR JANUS KINASE 3 JAK3 19p Missense 8 3 in N -terminus, 5 in catalytic negative; B-cell positive) Termination 2 catalytic Deletion 3 1 in N -terminus, 2 in catalytic Systemic lupus erythematosus AR LEUKOCYTE TYROSINE KINASE LTK 15q15.1-q Missense 1 catalytic Severe-combined immunodeficiency AR ZETA-CHAIN-ASSOCIATED ZAP70 2q Missense 2 catalytic (selective T-cell negative) PROTEIN KINASE Aberrant splicing 2 intronic leading to 3 amino acids insertion in catalytic Deletion 1 in catalytic Atypical lipodystrophy with AD V-AKT MURINE THYMOMA AKT2 19q13.1-q Missense 1 in pleckstrin homology insulin resistance and type 2 VIRAL ONCOGENE HOMOLOG 2 diabetes Donahue syndrome AR INSULIN RECEPTOR INSR 19p Missense 32 2 in signal peptide, 3 in catalytic, 8 in receptor-l (RL) 1, 7 in furin-like, 9 in RL 2, 3 in Fibronectin type III (FN3) Termination 4 1 in RL 1, 1 in RL 2, 1 5 to FN3, 1 in FN3 Deletion 1 entire gene Insulin-resistant diabetes AD INSULIN RECEPTOR INSR 19p Missense 17 1 in furin-like, 2 in mellitus with acanthosis RL- 2, 2 5 of catalytic nigricans, 10 in catalytic, 2 5 FN3 Termination 2 1 in RL 1, 1 before catalytic

6 Other disorders Hypogonadotropic hypogonadism AD FIBROBLAST GROWTH FACTOR RECEPTOR 1 Early-onset obesity, hyperphagia, AD NEUROTROPHIC TYROSINE developmental delay KINASE, RECEPTOR, TYPE 2 Gastrointestinal stromal AD PLATELET-DERIVED GROWTH tumor, familial FACTOR RECEPTOR, ALPHA Glycogen storage disease type XL PHOSPHORYLASE KINASE, 9A (types 1 and 2) LIVER, ALPHA-2 SUBUNIT Glycogen storage disease AR PHOSPHORYLASE KINASE, type 9C TESTIS/LIVER, GAMMA-2 Primary pigmented nodular AD PROTEIN KINASE, campadrenocortical disease DEPENDENT, REGULATORY, TYPE I, ALPHA Familial medullary thyroid AD REARRANGED DURING carcinoma Familial pheochromocytoma AD REARRANGED DURING Multiple endocrine neoplasia AD REARRANGED DURING type 2B Pseudohypo-aldosteronism AD PROTEIN KINASE, LYSINEtype 2 DEFICIENT 4 Cardiofaciocutaneous syndrome AD V-RAF MURINE SARCOMA VIRAL ONCOGENE HOMOLOG B1 Li-Fraumeni syndrome 2 AD CHECKPOINT KINASE 2, HOMOLOG OF S. POMBE Ins/del 2 exon 14 deletion, insertion of Alu element FGFR1 8p11.2-p Missense to signal peptide, 5 in catalytic (cytoplasmic), 2 in Ig-I set #2, 1 in Ig-I set #3 Termination 1 catalytic NTRK2 9q Missense 1 catalytic PDGFRA 4q Missense 2 catalytic PHKA2 Xp22.2-p Missense 14 NA Deletion 4 NA Termination 3 NA Aberrant splicing 1 exon 7 skipped Insertion 1 2 aa at residue 1111 PHKG2 16p12.1-p Missense 6 catalytic Termination 1 catalytic Ins/del 2 1 insertion--termination at residue 101; 1 deletion--termination at residue 110 PRKAR1A 17q Aberrant splicing 3 IVS1, IVS3, IVS6 RET 10q Missense 34 concentrated on cysteines; 18 around transmembrane region, 12 in the catalytic, 4 3 of transmembrane region Insertion 1 9 bp duplication in exon 8 RET 10q Missense 7 concentrated on cysteines; 1 in transmembrane region, rest in the catalytic RET 10q Missense 5 catalytic WNK4 17q21-q Missense 4 3 C -terminus of the coiled-coil, 1 in C -terminus of the protein BRAF 7q Missense in catalytic, 4 in phorbol esters/diacylglycerol binding CHEK2 22q Missense 2 FHA (Forkhead-associated)

7 Deletion 2 1 deletion leads to truncation at catalytic, 1 deletes n.1422 Wolcott-Rallison syndrome AR EUKARYOTIC TRANSLATION EIF2AK3 2p Missense 1 catalytic INITIATION FACTOR 2-ALPHA KINASE 3 Ins/del 2 leading to premature truncation at or near catalytic Aberrant splicing 1 IVS14 Termination 1 at quinoprotein alcohol dehydrogenase-like (non-cytoplasmic) Oguchi disease 1 AR G PROTEIN-DEPENDENT GRK1 13q Missense 2 catalytic RECEPTOR KINASE 1 Deletion 2 catalytic, site lost for posttranslation modification Endocrine-cerebroosteodysplasia AR INTESTINAL CELL KINASE ICK 6p Missense 1 catalytic Cardiofaciocutaneous syndrome AD MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1 MEK1 15q Missense 3 1 in coiled-coil, 2 in the catalytic Cardiofaciocutaneous syndrome AD MITOGEN-ACTIVATED PROTEIN KINASE KINASE 2 MEK2 19p Missense 3 2 in coiled-coil, 1 in catalytic Retinitis pigmentosa 38 AR MER TYROSINE KINASE MERTK 2q Missense 3 catalytic Termination 1 catalytic Aberrant splicing 2 IVS10 and IVS16 Deletion 1 at exon 15 resulting in truncation in catalytic Carney complex, Type 1 AD PROTEIN KINASE, camp- DEPENDENT, REGULATORY, TYPE I, ALPHA PRKAR1A 17q Missense 6 1 at N -terminus, 1 in regulatory subunit of type II PKA R-subunit, 3 in camp-binding 1, 1 in camp-binding 2 Aberrant splicing 3 at IVS6 and IVS8 and exon 6 skipped Deletion 6 1 N -terminus of camp-binding 1, 1 in camp-binding 2, 3 lead to truncations at the camp nucleotide-binding s, and 1 truncation at translation start site Noonan syndrome type 5 AD V-RAF-1 MURINE LEUKEMIA VIRAL ONCOGENE HOMOLOG 1 RAF1 3p Missense 14 5 in catalytic, rest is precatalytic LEOPARD syndrome type 2 AD V-RAF-1 MURINE LEUKEMIA VIRAL ONCOGENE HOMOLOG 1 RAF1 3p Missense 2 1 in catalytic, other is precatalytic

8 Congenital failure of autonomic control ND REARRANGED DURING Hirschsprung disease AD REARRANGED DURING Renal agenesis AD REARRANGED DURING Coffin-Lowry syndrome XL RIBOSOMAL PROTEIN S6 KINASE, 90-KD, polypeptide 3 RET 10q Missense 4 2 at N terminal, 1 between cadherin and kinase, 1 at C terminal RET 10q Missense 49 2 in signal peptide, 7 in N -terminus of cadherin, 6 in cadherin, 17 in catalytic, 17 in N -terminus of catalytic Deletion 1 Leads to catalytic truncation Termination 2 1 before and 1 in the cadherin site RET 10q Missense 8 1 at cadherin, 2 in btwn cadherin and catalytic, 3 at catalytic, 3 at C terminal RPS6KA3 Xp22.2-p Missense 12 9 in 1st catalytic, 2 in the 2nd catalytic, 1 in N after catalytic Aberrant splicing 5 4 point mutation and 1 insertion in introns Deletion 4 2 in 1st and 2 in 2nd catalytic Duplication 1 exons Termination 1 2nd catalytic Peutz-Jeghers syndrome AD SERINE/THREONINE PROTEIN KINASE 11 STK11 19p Missense 7 catalytic Termination 4 catalytic Deletion 9 1 deletion/inversion of exons 4-7, 2 resulting in 2 aa deletions in catalytic, deletion of aa 247, rest results in truncation at catalytic Aberrant splicing 1 at IVS3 LEGEND: MOI AR AD XL ND Ins/del serine/threonine kinase tyrosine kinase mode of inheritance autosomal recessive autosomal dominant X-linked not determined insertion/deletion mutation