Whole Exome Sequencing Gene package Neuronal migration disorders Version 3,

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1 Whole Exome Sequencing Gene package Neuronal migration disorders, version 3, Technical information DNA was enriched using Agilent SureSelect Clinical Research Exome V2 capture and paired end sequenced on the Illumina platform (outsourced). The aim is to obtain 8.1 Giga base pairs per exome with a mapped fraction of The average coverage of the exome is ~50x. Duplicate reads are excluded. Data are demultiplexed with bcl2fastq Conversion Software from Illumina. Reads are mapped to the genome using the BWA MEM algorithm (reference: bwa.sourceforge.net/). Variant detection is performed by the Genome Analysis Toolkit HaplotypeCaller (reference: The detected variants are filtered and annotated with Cartagenia software and classified with Alamut Visual. Additionally, MPLA analysis was performed for several (fragments of) genes involved in neuronal migration disorders (SALSA P061 Lissencephaly; MRC Holland). It is not excluded that pathogenic mutations are being missed using this technology. At this moment, there is not enough information about the sensitivity of this technique with respect to the detection of deletions and duplications of more than 5 nucleotides and of somatic mosaic mutations (all HGNC approved Phenotype description including phenotype ID(s) ACTB Baraitser Winter syndrome 1, ?Dystonia, juvenile onset, NM_ ACTG1 Baraitser Winter syndrome 2, NM_ Deafness 20/26, ADA2 Polyarteritis nodosa, childhood onset, NM_ ?Sneddon syndrome, ADAR Aicardi Goutieres syndrome 6, NM_ Dyschromatosis symmetrica hereditaria, ADGRG1 Polymicrogyria, bilateral frontoparietal, NM_ Polymicrogyria, bilateral perisylvian, AKT1 Breast cancer, somatic, NM_ Colorectal cancer, somatic, Cowden syndrome 6, Ovarian cancer, somatic, Proteus syndrome, somatic, {Schizophrenia, susceptibility to}, AKT3 Megalencephaly polymicrogyria polydactyly hydrocephalus syndrome 2, NM_ ANKLE2?Microcephaly 16, primary, NM_ AP1S2 Mental retardation syndromic 5, NM_ AP3B2 Epileptic encephalopathy, early infantile, 48, NM_ AP4B1 Spastic paraplegia 47, NM_ AP4E1 Spastic paraplegia 51, Stuttering, familial persistent, 1, NM_

2 Phenotype description including phenotype ID(s) AP4M1 Spastic paraplegia 50, NM_ AP4S1 Spastic paraplegia 52, NM_ ARFGEF2 Periventricular heterotopia with microcephaly, NM_ ARNT2?Webb Dattani syndrome, NM_ ARX Epileptic encephalopathy, early infantile, 1, NM_ Hydranencephaly with abnormal genitalia, Lissencephaly 2, Mental retardation 29 and others, Partington syndrome, Proud syndrome, ASNS Asparagine synthetase deficiency, NM_ ASPM Microcephaly 5, primary, NM_ ASXL1 Bohring Opitz syndrome, NM_ Myelodysplastic syndrome, somatic, ATAD3A Harel Yoon syndrome, NM_ ATAD3B No phenotype NM_ ATP6V0A2 Cutis laxa, type IIA, NM_ Wrinkly skin syndrome, ATR?Cutaneous telangiectasia and cancer syndrome, familial, NM_ Seckel syndrome 1, ATRIP No phenotype NM_ B3GALNT2 Muscular dystrophy dystroglycanopathy (congenital with brain and eye anomalies, type A, 11, NM_ B4GAT1 Muscular dystrophy dystroglycanopathy (congenital with brain and eye anomalies), type A, 13, NM_ CASK FG syndrome 4, NM_ Mental retardation and microcephaly with pontine and cerebellar hypoplasia, Mental retardation, with or without nystagmus, CCND2 Megalencephaly polymicrogyria polydactyly hydrocephalus syndrome 3, NM_ CDK5?Lissencephaly 7 with cerebellar hypoplasia, NM_ CDK5RAP2 Microcephaly 3, primary, NM_ CDK6?Microcephaly 12, primary, NM_ CENPJ Microcephaly 6, primary, NM_ ?Seckel syndrome 4, CEP135 Microcephaly 8, primary, NM_ CEP152 Microcephaly 9, primary, NM_ Seckel syndrome 5, CEP63?Seckel syndrome 6, NM_ CHMP1A Pontocerebellar hypoplasia, type 8, NM_ CIT Microcephaly 17, primary, NM_ CLP1 Pontocerebellar hypoplasia, type 10, NM_ COL18A1 Knobloch syndrome, type 1, NM_

3 Phenotype description including phenotype ID(s) COL4A1 Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, NM_ Brain small vessel disease with or without ocular anomalies, {Hemorrhage, intracerebral, susceptibility to}, Porencephaly 1, ?Retinal arteries, tortuosity of, COL4A2 {Hemorrhage, intracerebral, susceptibility to}, NM_ Porencephaly 2, CRADD Mental retardation 34, with variant lissencephaly, NM_ CRB2 Focal segmental glomerulosclerosis 9, NM_ Ventriculomegaly with cystic kidney disease, CSTB Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), NM_ CTC1 Cerebroretinal microangiopathy with calcifications and cysts, NM_ CTNND2 No phenotype NM_ DAB1 No phenotype NM_ DAG1 Muscular dystrophy dystroglycanopathy (congenital with brain and eye anomalies), type A, 9, NM_ Muscular dystrophy dystroglycanopathy (limb girdle), type C, 9, DCHS1 Mitral valve prolapse 2, NM_ Van Maldergem syndrome 1, DCX Lissencephaly, NM_ Subcortical laminal heteropia, DEPDC5 Epilepsy, familial focal, with variable foci 1, NM_ DKC1 Dyskeratosis congenita, NM_ DNMT3A Tatton Brown Rahman syndrome, NM_ DYNC1H1 Charcot Marie Tooth disease, axonal, type 20, NM_ Mental retardation 13, Spinal muscular atrophy, lower extremity predominant 1, AD, EIF2AK3 Wolcott Rallison syndrome, NM_ EMG1 Bowen Conradi syndrome, NM_ EML1 Band heterotopia, NM_ EOMES No phenotype NM_ ERCC1 Cerebrooculofacioskeletal syndrome 4, NM_ ERCC2 Cerebrooculofacioskeletal syndrome 2, NM_ Trichothiodystrophy 1, photosensitive, Xeroderma pigmentosum, group D, ERCC5 Cerebrooculofacioskeletal syndrome 3, Xeroderma pigmentosum, group G, Xeroderma pigmentosum, group G/Cockayne syndrome, NM_

4 Phenotype description including phenotype ID(s) ERCC6 Cerebrooculofacioskeletal syndrome 1, NM_ Cockayne syndrome, type B, De Sanctis Cacchione syndrome, {Lung cancer, susceptibility to}, {Macular degeneration, age related, susceptibility to, 5}, Premature ovarian failure 11, UV sensitive syndrome 1, ERMARD?Periventricular nodular heterotopia 6, NM_ FAT4 Hennekam lymphangiectasia lymphedema syndrome 2, NM_ Van Maldergem syndrome 2, FIG4 Amyotrophic lateral sclerosis 11, NM_ Charcot Marie Tooth disease, type 4J, ?Polymicrogyria, bilateral temporooccipital, Yunis Varon syndrome, FKRP Muscular dystrophy dystroglycanopathy (congenital with brain and eye anomalies), type A, 5, NM_ Muscular dystrophy dystroglycanopathy (congenital with or without mental retardation), type B, 5, Muscular dystrophy dystroglycanopathy (limb girdle), type C, 5, FKTN Cardiomyopathy, dilated, 1X, NM_ Muscular dystrophy dystroglycanopathy (congenital with brain and eye anomalies), type A, 4, Muscular dystrophy dystroglycanopathy (congenital without mental retardation), type B, 4, Muscular dystrophy dystroglycanopathy (limb girdle), type C, 4, FLNA Cardiac valvular dysplasia, NM_ Congenital short bowel syndrome, FG syndrome 2, Frontometaphyseal dysplasia 1, Heterotopia, periventricular, Intestinal pseudoobstruction, neuronal, Melnick Needles syndrome, Otopalatodigital syndrome, type I, Otopalatodigital syndrome, type II, Terminal osseous dysplasia, FLVCR2 Proliferative vasculopathy and hydraencephaly hydrocephaly syndrome, NM_ FRMD4A?Corpus callosum, agenesis of, with facial anomalies and cerebellar ataxia, NM_ GNAQ Capillary malformations, congenital, 1, somatic, mosaic, NM_ Sturge Weber syndrome, somatic, mosaic, HNRNPK Au Kline syndrome, NM_ IBA57?Multiple mitochondrial dysfunctions syndrome 3, NM_ ?Spastic paraplegia 74, IER3IP1 Microcephaly, epilepsy, and diabetes syndrome, NM_ IFIH1 Aicardi Goutieres syndrome 7, Singleton Merten syndrome 1, NM_

5 Phenotype description including phenotype ID(s) INTS8 No phenotype NM_ ISPD Muscular dystrophy dystroglycanopathy (congenital with brain and eye anomalies), type A, 7, NM_ Muscular dystrophy dystroglycanopathy (limb girdle), type C, 7, ITSN1 No phenotype NM_ JAM3 Hemorrhagic destruction of the brain, subependymal calcification, and cataracts, NM_ KATNB1 Lissencephaly 6, with microcephaly, NM_ KIF11 Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation, NM_ KIF1BP Goldberg Shprintzen megacolon syndrome, NM_ KIF2A Cortical dysplasia, complex, with other brain malformations 3, NM_ KIF5C Cortical dysplasia, complex, with other brain malformations 2, NM_ KIF7 Acrocallosal syndrome, NM_ ?Al Gazali Bakalinova syndrome, ?Hydrolethalus syndrome 2, Joubert syndrome 12, KNL1 Microcephaly 4, primary, NM_ KPTN Mental retardation 41, NM_ L1CAM CRASH syndrome, NM_ Corpus callosum, partial agenesis of, Hydrocephalus due to aqueductal stenosis, Hydrocephalus with Hirschsprung disease, Hydrocephalus with congenital idiopathic intestinal pseudoobstruction, MASA syndrome, LAMA1 Poretti Boltshauser syndrome, NM_ LAMA2 Muscular dystrophy, congenital merosin deficient, NM_ Muscular dystrophy, congenital, due to partial LAMA2 deficiency, LAMB1 Lissencephaly 5, NM_ LAMC1 No phenotype NM_ LAMC3 Cortical malformations, occipital, NM_ LARGE1 Muscular dystrophy dystroglycanopathy (congenital with brain and eye anomalies), type A, 6, NM_ Muscular dystrophy dystroglycanopathy (congenital with mental retardation), type B, 6, LARP7 Alazami syndrome, NM_ MCPH1 Microcephaly 1, primary, NM_ MED17 Microcephaly, postnatal progressive, with seizures and brain atrophy, NM_ MPDZ Hydrocephalus, nonsyndromic 2, NM_ MYCN Feingold syndrome 1, NM_ NBN Aplastic anemia, NM_ Leukemia, acute lymphoblastic, Nijmegen breakage syndrome, NDE1 Lissencephaly 4 (with microcephaly), NM_ ?Microhydranencephaly, NID1 No phenotype NM_

6 Phenotype description including phenotype ID(s) NIN?Seckel syndrome 7, NM_ NPRL3 Epilepsy, familial focal, with variable foci 3, NM_ NSDHL CHILD syndrome, NM_ CK syndrome, OCLN Pseudo TORCH syndrome 1, NM_ PAFAH1B1 Lissencephaly 1, NM_ Subcortical laminar heterotopia, PAX6 Aniridia, NM_ Anterior segment dysgenesis 5, multiple subtypes, Cataract with late onset corneal dystrophy, ?Coloboma of optic nerve, ?Coloboma, ocular, Foveal hypoplasia 1, Keratitis, ?Morning glory disc anomaly, Optic nerve hypoplasia, PCNT Microcephalic osteodysplastic primordial dwarfism, type II, NM_ PHC1?Microcephaly 11, primary, NM_ PI4KA Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, NM_ PIK3CA Breast cancer, somatic, NM_ CLOVE syndrome, somatic, Colorectal cancer, somatic, Cowden syndrome 5, Gastric cancer, somatic, Hepatocellular carcinoma, somatic, Keratosis, seborrheic, somatic, Megalencephaly capillary malformation polymicrogyria syndrome, somatic, Nevus, epidermal, somatic, Nonsmall cell lung cancer, somatic, Ovarian cancer, somatic, PIK3R2 Megalencephaly polymicrogyria polydactyly hydrocephalus syndrome 1, NM_ PLK4 Microcephaly and chorioretinopathy, 2, NM_ PNKP Ataxia oculomotor apraxia 4, NM_ Microcephaly, seizures, and developmental delay, POLR3B Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, NM_ POMGNT1 Muscular dystrophy dystroglycanopathy (congenital with brain and eye anomalies), type A, 3, Muscular dystrophy dystroglycanopathy (congenital with mental retardation), type B, 3, Muscular dystrophy dystroglycanopathy (limb girdle), type C, 3, Retinitis pigmentosa 76, NM_

7 Phenotype description including phenotype ID(s) POMT1 Muscular dystrophy dystroglycanopathy (congenital with brain and eye anomalies), type A, 1, NM_ Muscular dystrophy dystroglycanopathy (congenital with mental retardation), type B, 1, Muscular dystrophy dystroglycanopathy (limb girdle), type C, 1, POMT2 Muscular dystrophy dystroglycanopathy (congenital with brain and eye anomalies), type A, 2, NM_ Muscular dystrophy dystroglycanopathy (congenital with mental retardation), type B, 2, Muscular dystrophy dystroglycanopathy (limb girdle), type C, 2, PTEN Bannayan Riley Ruvalcaba syndrome, NM_ Cowden syndrome 1, Endometrial carcinoma, somatic, {Glioma susceptibility 2}, Lhermitte Duclos syndrome, Macrocephaly/autism syndrome, Malignant melanoma, somatic, {Meningioma}, PTEN hamartoma tumor syndrome {Prostate cancer, somatic}, Squamous cell carcinoma, head and neck, somatic, VATER association with macrocephaly and ventriculomegaly, PTF1A Pancreatic agenesis 2, NM_ Pancreatic and cerebellar agenesis, PYCR2 Leukodystrophy, hypomyelinating, 10, NM_ QARS Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy, NM_ RAB18 Warburg micro syndrome 3, NM_ RAB3GAP1 Warburg micro syndrome 1, NM_ RAB3GAP2 Martsolf syndrome, NM_ Warburg micro syndrome 2, RAD50 Nijmegen breakage syndrome like disorder, NM_ RARS2 Pontocerebellar hypoplasia, type 6, NM_ RBBP8 Jawad syndrome, NM_ Pancreatic carcinoma, somatic Seckel syndrome 2, RBM10 TARP syndrome, NM_ RELN {Epilepsy, familial temporal lobe, 7}, NM_ Lissencephaly 2 (Norman Roberts type), RNASEH2A Aicardi Goutieres syndrome 4, NM_ RNASEH2B Aicardi Goutieres syndrome 2, NM_ RNASEH2C Aicardi Goutieres syndrome 3, NM_ RNASET2 Leukoencephalopathy, cystic, without megalencephaly, NM_ RNU4ATAC Microcephalic osteodysplastic primordial dwarfism, type I, Roifman syndrome, NR_ No coverag0 0 0

8 Phenotype description including phenotype ID(s) RTEL1 Dyskeratosis congenita 4, NM_ Dyskeratosis congenita 5, Pulmonary fibrosis and/or bone marrow failure, telomere related, 3, RTTN Microcephaly, short stature, and polymicrogyria with seizures, NM_ SAMHD1 Aicardi Goutieres syndrome 5, NM_ ?Chilblain lupus 2, SHOC2 Noonan like syndrome with loose anagen hair, NM_ SLC25A19 Microcephaly, Amish type, NM_ Thiamine metabolism dysfunction syndrome 4 (progressive polyneuropathy type), SMPD4 No phenotype NM_ SNAP29 Cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome, NM_ SRPX2?Rolandic epilepsy, mental retardation, and speech dyspraxia, NM_ STAMBP Microcephaly capillary malformation syndrome, NM_ STIL Microcephaly 7, primary, NM_ STRADA Polyhydramnios, megalencephaly, and symptomatic epilepsy, NM_ TBC1D20 Warburg micro syndrome 4, NM_ TBC1D24 DOOR syndrome, NM_ Deafness 86, Deafness 65, Epileptic encephalopathy, early infantile, 16, Myoclonic epilepsy, infantile, familial, TBC1D7 Macrocephaly/megalencephaly syndrome, NM_ TMEM5 Muscular dystrophy dystroglycanopathy (congenital with brain and eye anomalies), type A, 10, NM_ TMTC3 Lissencephaly 8, NM_ TMX2 No phenotype NM_ TRAIP Seckel syndrome 9, NM_ TREX1 Aicardi Goutieres syndrome 1, dominant and recessive, NM_ Chilblain lupus, {Systemic lupus erythematosus, susceptibility to}, Vasculopathy, retinal, with cerebral leukodystrophy, TSC1 Focal cortical dysplasia, type II, somatic, NM_ Lymphangioleiomyomatosis, Tuberous sclerosis 1, TSC2?Focal cortical dysplasia, type II, somatic, NM_ Lymphangioleiomyomatosis, somatic, Tuberous sclerosis 2, TSEN54 Pontocerebellar hypoplasia type 2A, NM_ Pontocerebellar hypoplasia type 4, ?Pontocerebellar hypoplasia type 5, TUBA1A Lissencephaly 3, NM_ TUBA8 Polymicrogyria with optic nerve hypoplasia, NM_

9 Phenotype description including phenotype ID(s) TUBB Cortical dysplasia, complex, with other brain malformations 6, NM_ Symmetric circumferential skin creases, congenital, 1, TUBB2A Cortical dysplasia, complex, with other brain malformations 5, NM_ TUBB2B Polymicrogyria, symmetric or asymmetric, NM_ TUBB3 Cortical dysplasia, complex, with other brain malformations 1, NM_ Fibrosis of extraocular muscles, congenital, 3A, TUBB4A Dystonia 4, torsion, NM_ Leukodystrophy, hypomyelinating, 6, TUBG1 Cortical dysplasia, complex, with other brain malformations 4, NM_ TUBGCP4 Microcephaly and chorioretinopathy, 3, NM_ TUBGCP6 Microcephaly and chorioretinopathy, 1, NM_ VLDLR Cerebellar hypoplasia and mental retardation with or without quadrupedal locomotion 1, NM_ VPS13B Cohen syndrome, NM_ VRK1 Pontocerebellar hypoplasia type 1A, NM_ WASHC5 Ritscher Schinzel syndrome 1, NM_ Spastic paraplegia 8, WDR4 No phenotype NM_ WDR62 Microcephaly 2, primary, with or without cortical malformations, NM_ WDR73 Galloway Mowat syndrome, NM_ WDR81 Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 2, NM_ YWHAE No phenotype NM_ ZIC1 Craniosynostosis 6, NM_ ZIC2 Holoprosencephaly 5, NM_ ZIC4 No phenotype NM_ Gene symbols according HGCN release used: "No phenotypes" indicates a gene without a current association phenotypes between "[ ]", indicate "nondiseases," mainly genetic variations that lead to apparently abnormal laboratory test values phenotypes between "{}", indicate risk factors phenotypes with a question mark, "?", before the disease name indicates an unconfirmed or possibly spurious mapping The statistics above are based on a set of 96 samples Median is the of the mean sequence over the protein coding exons (±10bp flanking introns) of the longest transcript % Covered 10x describes the percentage of a gene s coding sequence (±10bp flanking introns) that is covered at least 10x % Covered 20x describes the percentage of a gene s coding sequence (±10bp flanking introns) that is covered at least 20x