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ORIGINAL ARTICLE
Year : 2021  |  Volume : 69  |  Issue : 6  |  Page : 1729-1736

Assessing Utility of Clinical Exome Sequencing in Diagnosis of Rare Idiopathic Neurodevelopmental Disorders in Indian Population


1 RIGE's Institute of Human Genetics, FRIGE House, Jodhpur Gam Road, Satellite, Ahmedabad, Gujarat, India
2 Strand Life Sciences Private Limited, Bengaluru, Karnataka, India
3 Mayflower Woman's Hospital, Ahmedabad, Gujarat, India
4 Sheth V. S. General Hospital and NHL Municipal Medical College, Ahmedabad, Gujarat, India
5 Sir Takhtasinhji General Hospital, Bhavnagar, Gujarat, India

Date of Submission02-Apr-2020
Date of Decision16-Oct-2020
Date of Acceptance14-Dec-2020
Date of Web Publication23-Dec-2021

Correspondence Address:
Dr. Harsh Sheth
FRIGE's Institute of Human Genetics, FRIGE House, Satellite, Ahmedabad - 380 015. Gujarat
India
Jayesh Sheth
FRIGE's Institute of Human Genetics, FRIGE House, Satellite, Ahmedabad - 380 015. Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.333475

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 » Abstract 


Background: Neurological diseases are phenotypically and genotypically heterogeneous. Clinical exome sequencing (CES) has been shown to provide a high diagnostic yield for these disorders in the European population but remains to be demonstrated for the Indian population.
Objective: The study aimed to understand the utility of clinical exome sequencing for the diagnosis of neurodevelopmental disorders.
Materials and Methods: A cohort of 19 idiopathic patients with neurological phenotypes, primarily intellectual disability and developmental delay, were recruited. CES covering 4620 genes was performed on all patients. Candidate variants were validated by Sanger sequencing.
Results: CES in 19 patients provided identified 21 variants across 16 genes which have been associated with different neurological disorders. Fifteen variants were reported previously and 6 variants were novel to our study. Eleven patients were diagnosed with autosomal dominant de novo variants, 7 with autosomal recessive and 1 with X-linked recessive variants. CES provided definitive diagnosis to 10 patients; hence, the diagnostic yield was 53%.
Conclusion: Our study suggests that the diagnostic yield of CES in the Indian population is comparable to that reported in the European population. CES together with deep phenotyping could be a cost-effective way of diagnosing rare neurological disorders in the Indian population.


Keywords: Clinical exome sequencing, de novo inheritance, developmental delay, diagnostic yield, intellectual disability, neurological disorders
Key Messages: Clinical exome sequencing is a cost-effective diagnostic tool for rare idiopathic neurodevelopmental disorders in Indian population.


How to cite this article:
Sheth H, Pancholi D, Bhavsar R, Mannan AU, Ganapathy A, Chowdhury M, Shah S, Solanki D, Sheth F, Sheth J. Assessing Utility of Clinical Exome Sequencing in Diagnosis of Rare Idiopathic Neurodevelopmental Disorders in Indian Population. Neurol India 2021;69:1729-36

How to cite this URL:
Sheth H, Pancholi D, Bhavsar R, Mannan AU, Ganapathy A, Chowdhury M, Shah S, Solanki D, Sheth F, Sheth J. Assessing Utility of Clinical Exome Sequencing in Diagnosis of Rare Idiopathic Neurodevelopmental Disorders in Indian Population. Neurol India [serial online] 2021 [cited 2022 Jan 26];69:1729-36. Available from: https://www.neurologyindia.com/text.asp?2021/69/6/1729/333475




The brain is an incredibly complex organ consisting of a plethora of interconnected cell types. During development and day-to-day functioning, a variety of neurons and numerous proteins are required in the right amount at the right place and at the right time. Hence, any pathogenic mutation affecting genes that are involved in the production of these proteins can have consequences on brain development and functioning. Neurological disorders are conditions in which the motor, sensory, and cognitive functions decline due to variation(s) in the genotype of one or more genes involved in the functions of neurons, spinal cord, and peripheral nerves.[1] They are ranked as the leading disorder to cause 10.2% of global disability-adjusted-life-years compared to 7.3% in 1990, and second-leading disorder responsible for 16.8% of the global deaths.[2],[3] These are clinically heterogeneous and genetically diverse group of disorders affecting all age group with sporadic (autosomal dominant) or acquired (autosomal or X-linked recessive) inheritance. This makes the diagnosis more challenging using the conventional techniques and often deprives the patient of proper treatment. Furthermore, genetic counselling during pregnancy becomes challenging when families approach for prenatal diagnosis.

An extensive genotypic overlap amongst a range of neurodegenerative disease involving neuropathy, myopathy, epileptic encephalopathy, ataxia, paraphasia, intellectual disability, and sensory impairment hampers the genetic diagnosis and makes it difficult to target specific genes for study.[4] For instance, EpilepsyGene, designed in 2015, includes 499 genes and 3931 variants associated with epilepsy.[5] Moreover, with respect to intellectual disability, 528 confirmed genes and 628 candidate genes are reported.[6] Different variations in a single gene can lead to different clinical entities in neurological disorders. An ideal example is of a variation in LIS1 gene (also called as PAFAH1B1: platelet activating factor acetyl hydrolase 1b regulatory subunit 1 gene). A small deletion in LIS1 gene leads to an isolated lissencephaly sequence. However, a large deletion covering LIS1 gene and neighboring genes causes Miller-Dieker syndrome.[7] Both the diseases exhibit similar clinical traits except for the facial dysmorphism, as observed only in Miller-Dieker syndrome.[8] Thus, identification of the genetic cause of a neurological disease using conventional techniques like polymerase chain reaction (PCR) and Sanger sequencing (one-loci-at-a-time approach) seems true in the diseases with well-established genotypic-phenotypic correlation. However, many neurological disorders, even after a meticulous evaluation, remain undiagnosed due to the presence of mild or unusual traits, and lack of precise molecular basis. Sanger sequencing approach is laborious, expensive and falls short in detecting nucleotide repeat expansions, large indels, or copy number variations.

Clinical and whole exome sequencing (CES and WES) has facilitated clinical utility in identifying and characterizing the genes and variants involved in the clinical presentation of the idiopathic neurological disorders because of their ability to sequence multiple genes at a time in a cost-effective manner. With the application of WES, the diagnosis rate in clinical practice has increased which helps in early diagnosis, prognosis, reproductive counselling, medical management and prenatal diagnosis.[9] Furthermore, it is useful in the diagnosis of the etiologically misleading neurological disorders that give false positive result using conventional techniques.

However, most of the studies carried out to date have been in the white European population and western healthcare settings. The diagnostic utility and cost-effectiveness of WES and CES is currently unknown for the Indian population. Since the goal of introducing any technique in clinical practice is to maximize diagnostic yield and minimize cost to the patient, our aim was to assess the utility of CES in diagnosing rare idiopathic neurological disorders in a cohort of 19 patients from the Indian population.


 » Methods Top


Patient recruitment

The present cohort-based study comprised of 19 unrelated idiopathic patients with variable neurodevelopmental phenotypes including intellectual disability and developmental delay that were referred between 2015 and 2017. All patients were evaluated according to the clinically validated developmental scales by their referring clinicians. Each referring physician provided details on their phenotype, particularly: developmental, neurological, behavioral and epilepsy history, accompanied by imaging data if available. At the time of recruitment, a pro forma comprising of patient's clinical details including history of clinical test performed previously, family history, parent's consanguinity and ethnicity was recorded.

The present study has been approved by the institutional ethics committee [FRIGE's Institute of Human Genetics] with approval number FRIGE/IEC/14/2016 dated 19th November 2016. This process is in accordance with the declaration of Helsinki. An informed consent for investigation was obtained from the family of the proband at the time of enrollment for the study [This was in accordance with the requirement of the institutional ethics committee]. An informed consent for publication was also obtained from the individuals included in the submission [This was in accordance with the requirement of the institutional ethics committee]. Informed written consent was obtained from parents for publication of the proband's clinical details and/or clinical images.

DNA extraction

Four milliliters of whole blood drawn from each patient in an EDTA vacutainer was used for the genomic DNA isolation using the salting-out technique. DNA was quantified using QIAxpert (Qiagen, Germany). To ensure the absence of any salts or inhibitors in downstream applications, all DNA samples were purified using Genomic DNA Clean and Concentrator™-25 kit (Zymo Research, U.S.A) as per the manufacturer's instructions. High quality DNA was subsequently used for clinical exome and Sanger sequencing.

Clinical exome sequencing and variant validation

DNA from probands were sequenced for clinical exome by Strand Life Sciences, India. Exon and splice site regions of >4600 genes associated with known inherited diseases were captured using TruSight One kit (Illumina, USA) [Supplementary File 1]. Paired-end 150 bp sequencing was carried out on Illumina HiSeq 2500 platform (Illumina, USA) in accordance with the manufacturer's protocols, with an average coverage of 100x. Bioinformatic analysis was subsequently carried out using an in-house pipeline developed by Strand Life Sciences. Briefly, unique sequencing reads passing quality filters were aligned against the reference genome (GRCh37/hg19) using a local alignment tool called STRAND® NGS v2.5 (Strand Life Sciences, India). Single nucleotide variants (SNVs) and small indels were called using STRAND® NGS v2.5 variant caller at loci that were covered by at least 10 reads and had a variant allele in at least two reads. Copy number variants (CNVs) were called following sequence coverage normalization and Z-score estimation for a panel of regions against a profile of multiple control samples in the in-house database. All the variants were exported to StrandOmics v5.0 (Strand Life Sciences, India) where variant annotation, filtering and prioritization was carried out. Variants were filtered based on their impact on gene (missense, nonsense, frameshift or canonical splice site variants) and a minor allele frequency of <1% in databases (1000 Genomes Database, HapMap Database, Exome Variant Server, Exome Aggregation Consortium, gnomAD and in-house database consisting data of >1500 people) Lastly, candidate variants were annotated according to the ACMG-AMP classification into 5 classes: benign, likely binging, uncertain significance, likely pathogenic and pathogenic using semi-automated InterVar.[10]

Candidate SNVs were validated using bi directional Sanger sequencing on the SeqStuido Genetic Analyzer platform (Applied Biosystems, USA), according to the manufacturer's protocols. Primer sequences were designed using Primer3 v0.4.0 online tool (http://bioinfo.ut.ee/ primer3 0.4.0/) and PCR conditions used for validation are listed in [Supplementary Table 1] and [Supplementary File 3].




 » Results Top


Clinical presentation

Out of 19 patients in our cohort, 12 were males and 9 were females, with the mean age at the time of study being 10.8 years (range 9 months to 45 years; [Figure 1]). Recurrent features included global developmental delay, intellectual disability and muscle abnormalities such as hypotonia, walking difficulty and poor control of neck and body in these patients [Table 1], [Supplementary Table 2]. Approximately 30% of the patients also suffered from seizures and epilepsy. Genomic DNA from all patients were analyzed by clinical exome sequencing.
Figure 1: Family pedigree of probands. The square box represents male and the circle represents female. The patient under investigation is marked with an arrow. The numeric value under each pedigree depicts the age of the patient. Filled black squares and circles correspond to the affected status of the person and half black squares and circles correspond to carrier status of the person

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Table 1: Clinical details and demographic profile of the patients with neurological disorder

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Genetic analysis of patients

In our cohort of 19 patients with neurodevelopmental disorders, we identified 21 variants across 16 genes which have been associated with different neurological disorders [Table 2], [Supplementary File 2]. Interestingly, 15 of the 21 variants have been reported previously in the literature and the remaining were novel to our study. Out of 21 variants, 14 were missense, 3 splice site, 2 frameshift and 2 nonsense variants. Out of 19 patients, 7 patients were identified with autosomal recessive, 1 with X-linked recessive and 11 with autosomal dominant disorders. Of 11 patients with autosomal dominant de novo variants, 8 (73%) have been described previously in the literature [Table 2]. Three novel de novo variants included 2 missense variants in genes SCN1A (c. 5351T>A/p.Val1784Asp) and BSCL2 (c.461C>T/p.Ser154Leu), and a frameshift mutation that led to a premature stop in gene SCN2A (c.1153delT/p.Phe385SerfsTer8). With the unavailability of parental samples for all 11 patients with presumed de novo mutations, Sanger sequencing for de novo mutation confirmation was not carried out.
Table 2: Candidate variants identified by clinical exome sequencing in patients with idiopathic neurological disorders

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Of interest, out of the 6 novel mutations identified in the current study, 1 was classed as pathogenic (SCN2A c. 1153delT), 2 as likely pathogenic (SCN1A c.5351T>A and BSCL2 c. 461C>T) and 3 as variants of unknown significance (PGAP1 c. 2286+5G>A, FBXO7 c.520T>A and AFG3L2 c.1951A>G). Furthermore, segregation analysis of PGAP1 c.2286+5G>A variant showed parents to be heterozygous carriers and affected siblings to be homozygous for the variants. However, due to the absence of parental DNA for the patient with AFG3L2 c.1951A>G mutation, segregation analysis was not carried.

Overall, out of 21 variants, 4 were classed as pathogenic, 9 as likely pathogenic and 8 as variant of unknown significance according to the ACMG-AMP guidelines. With the clinical exome sequencing approach, we were able to provide definitive diagnosis to 10 patients; hence, our diagnostic yield with this approach was 53%.

It is important to note that the impact on medical management and treatment strategies following the provision of genetic diagnosis to patients and their healthcare providers was not recorded as it was not within the study's aims and remit.


 » Discussion and Conclusions Top


In the current study, our aim was to assess the utility of clinical exome sequencing in the diagnosis of rare neurological disorders in India. Exome sequencing of 19 patients with intellectual disability and/or developmental delay provided confirmed diagnosis of 10 patients, whereby, ~50% of the mutations were of de novo origin. The study also elucidated 15 rare diseases that were diagnosed in these patients that would have otherwise been difficult to diagnose with cheaper but lower-resolution orthogonal methods such as microarray and karyotyping.

Eleven patients were identified carrying autosomal dominant de novo mutations, which is a known disease mechanism in rare neurological disorders.[26],[27] Furthermore, 8 out of 11 variants have previously been reported in other studies, thereby, further strengthening the evidence for the role of these variants in causing respective diseases. It is noteworthy that out of these 8 known de novo variants, 50% were missense variants and the remaining were either splice site or nonsense mutations. This finding has direct implication on genetic counselling whereby, de novo missense mutations can be associated with incomplete penetrance, whereas, nonsense and splice site mutations are not, as shown for SCN1A gene.[28]

Despite finding known disease associated variants in majority of the patients, our study identified 6 novel variants in 6 genes- SCN1A, SCN2A, PGAP1, FBOX7, AFG3L2 and BSCL2. Diseases associated with these genes include Dravet syndrome (OMIM#607208), early infantile epileptic encephalopathy type 11 (OMIM#613721), mental retardation type 42 (OMIM#615802), Parkinson disease 15 (OMIM#260300), spastic ataxia type 5 (OMIM#614487) and hereditary spastic paraplegia (OMIM#270685), respectively. Whilst 3 of the 6 variants are classed as pathogenic or likely pathogenic according to the ACMG-AMP classification,[29] they are to be interpreted with caution as these variants would require replication in other large patient and control cohorts, and functional follow-up to assess their pathogenicity as well as disease association.[30] Of all the variants associated with genes having autosomal recessive inheritance, one-third (3 out of 9) were novel to the study cohort whereas none of the variants associated with genes having X-linked recessive inheritance were novel. This suggests an intriguing hypothesis of a reduced probability of finding novel recessive genes compared to dominant genes in neurological diseases in the Indian population; one that is supported by the data available from studies in the European population.[27]

Interestingly, the diagnostic yield of clinical exome in our cohort was 53%, which is in concordance with the published literature.[27] However, this needs to be placed in contrast with the role of de novo copy number variants (CNVs) that also play role in neurological disorder pathogenesis.[27] Genomic microarray-based studies have shown a strong correlation between the number of genes affected by a CNV and phenotypic severity.[27],[31] Indeed, microarray-based studies have shown presence of rare, autosomal dominant form of de novo CNVs in approximately 10% of patients.[27] Whilst microarray has been the mainstay for detection of CNVs, exome sequencing based large CNV detection (>400 kb) are increasingly becoming prominent in diagnosing neurological disorders.[32] Furthermore, it is estimated that 45-60 de novo single nucleotide variants occur per genome per generation whereas the frequency of de novo >500 kb CNVs is approximately 0.01 per genome per generation.[33],[34] This difference in mutation rates together with difference in mutation detection abilities could explain an enhancement in the diagnostic yield of exome sequencing by 24-33% over microarray.[27] Therefore, utilization of an exome sequencing technique in identifying de novo variants (both SNV and CNV) compared to microarray-based approach in identifying only de novo CNVs in neurological diseases is likely to be an attractive approach.

Whilst the current study highlights several benefits of using an exome sequencing based approach in diagnosing neurological diseases, there are some caveats which needs to be highlighted. First, the diagnostic yield of 53% in our study could be misleading if taken at face value. Indeed, overall diagnostic yield has been reported between 50-70% in diagnosing moderate to severe intellectual disability diseases,[27] depth and quality of patient phenotyping can impact diagnostic yield.[35] The current study carried out an in-depth patient phenotype which may have aided in interpreting genotype data and disease diagnosis. Second, 11 patients in whom de novo SNVs were identified, Sanger validation for the mode of inheritance confirmation wasn't carried out due to the unavailability of parental samples. Without Sanger sequencing confirmation in parental samples, it is conceivable that these variants may have been inherited from one of the parents. However, since these disorders have a significant impact on patient's fitness,[27] it is unlikely for either of the parents to be a carrier of these mutations. Hence, despite the absence of parental samples, replication of variants from the literature together with heterozygous status in the patient's sample suggests these variants to be likely of de novo origin. Third, the current study had a small sample size compared to the large multicenter project like Deciphering Developmental Disorders (https://www.ddduk.org). However, the study was aimed to assess the utility of clinical exome sequencing in the Indian population rather than identification of novel genes and pathways involved in neurological disorders, hence had a requirement for a small sample size. Fourth, the current study did not record changes in the clinical management following release of genetic diagnostic results to patients and their healthcare providers. It is well known that precise genetic diagnosis can have a major impact on clinical management, such as- change from antiepileptic drug to oxcarbazepine in patients diagnosed with SCN8A mutation and recurrence risk estimation in subsequent pregnancy based on the mode of inheritance.[36],[37]

Genetic studies have significantly improved in the past decade and consequently, there has been a substantial improvement in the diagnosis of neurological disorders. Due to the phenotypic and genetic heterogeneity of neurological disorders, it is required to carry out hypothesis-free exome-wide approaches as a first-tier diagnostic test. Even with the current lack of knowledge around all neurological disease causing genes and pathogenic variants, it seems that de novo mutations are the main cause of neurological diseases. Results from our study suggest carrying out deep phenotyping along with clinical exome sequencing as a first-line diagnostic test in neurological disorders in the Indian population.

Acknowledgements

This work is partly supported by Gujarat State Biotechnology Mission (GSBTM) [grant no.: GSBTM/MD/PROJECTS/SSA/505/4865/2016-17]. The funding agency was not involved in the study design, specimen collection, analysis, interpretation and preparation of the manuscript. The authors are profoundly grateful to the patients and their family members for participating in the study.

Financial support and sponsorship

This work is partly supported by Gujarat State Biotechnology Mission (GSBTM) [grant no.: GSBTM/MD/PROJECTS/SSA/505/4865/2016-17]. The funding agency was not involved in the study design, specimen collection, analysis, interpretation and preparation of the manuscript.

Conflicts of interest

There are no conflicts of interest.


 » Supplementary File 1: Clinical exome panel genes. The list presents 4620 genes covered in clinical exome test Top


List of genes present in the clinical exome test

A2M, A4GALT, A4GNT, AAAS, AADAC, AADACL2, AANAT, AARS, AARS2, AASS, ABAT, ABCA1, ABCA10, ABCA12, ABCA13, ABCA2, ABCA3, ABCA4, ABCA7, ABCB1, ABCB11, ABCB4, ABCB6, ABCB7, ABCC1, ABCC11, ABCC2, ABCC3, ABCC4, ABCC6, ABCC8, ABCC9, ABCD1, ABCD3, ABCD4, ABCG1, ABCG2, ABCG5, ABCG8, ABHD12, ABHD5*, ABI3BP, ABO, ACACA, ACACB, ACAD8, ACAD9, ACADL, ACADM, ACADS, ACADSB, ACADVL, ACAN, ACAT1, ACAT2, ACBD5, ACBD6, ACCS, ACE, ACHE, ACLY, ACO2, ACOX1, ACP5, ACSF3, ACSL4, ACSL5, ACSM2B, ACSM3, ACTA1, ACTA2, ACTB, ACTC1, ACTG1, ACTN2, ACTN3, ACTN4, ACVR1, ACVR1B*, ACVR1C, ACVR2B, ACVRL1, ACY1, ADA, ADAM10, ADAM12, ADAM17, ADAM19, ADAM33, ADAM7, ADAM9, ADAMTS10, ADAMTS13, ADAMTS16, ADAMTS17*, ADAMTS18, ADAMTS2*, ADAMTSL2, ADAMTSL3, ADAMTSL4, ADAR, ADARB1, ADC, ADCK3, ADCY10, ADCY3, ADCY5*, ADCY6, ADCY9*, ADCYAP1, ADD1, ADH1B, ADH1C, ADH4, ADH5, ADH7, ADIPOQ*, ADIPOR1, ADK, ADM, ADNP, ADORA1, ADORA2A, ADORA3, ADRA1A, ADRA2B, ADRB2, ADRB3, ADRBK2, ADSL, ADTRP, AFF2, AFF3, AFG3L2*, AFP, AGA, AGBL4, AGER, AGGF1, AGK, AGL, AGMO, AGO1, AGO2, AGPAT2, AGPS, AGRN, AGRP, AGT, AGTR1, AGTR2, AGXT, AGXT2, AHCY, AHI1, AHR, AHRR, AHSG, AHSP, AICDA, AIF1, AIFM1, AIMP1, AIP, AIPL1, AIRE*, AK1, AK2, AKAP10, AKAP13, AKAP2, AKAP9, AKR1B1, AKR1C2, AKR1C3, AKR1C4, AKR1D1, AKR7A2*, AKR7A3, AKT1, AKT2, AKT3, ALAD, ALAS2, ALB, ALCAM, ALDH16A1, ALDH18A1, ALDH1A1, ALDH1A2, ALDH2, ALDH3A2, ALDH4A1, ALDH5A1*, ALDH6A1, ALDH7A1, ALDOA, ALDOB, ALG1, ALG10B, ALG11, ALG12, ALG13, ALG2, ALG3, ALG6, ALG8, ALG9, ALK*, ALMS1, ALOX12, ALOX12B, ALOX15, ALOX5, ALOX5AP, ALOXE3, ALPL, ALS2, ALS2CL, ALX1, ALX4, AMACR, AMELX, AMER1, AMH*, AMHR2, AMN*, AMPD1, AMPD3, AMT, ANAPC1, ANG, ANGPT1, ANGPTL3*, ANGPTL4, ANGPTL5, ANK1, ANK2, ANK3, ANKH, ANKK1, ANKRD1, ANKRD11, ANKRD26, ANKS1A, ANKS1B, ANO10, ANO5, ANO6, ANO7, ANTXR1*, ANTXR2, ANXA11, ANXA5, AOAH, AOC1, AP1S1, AP1S2, AP3B1, AP3B2, AP4B1, AP4E1, AP4M1, AP4S1*, AP5Z1, APAF1, APBA2, APBB1, APBB3, APC, APCDD1*, APEX1, APH1A, APH1B, APOA1, APOA2, APOA4, APOA5, APOB, APOBEC3B, APOBEC3G, APOBEC3H, APOC1, APOC2, APOC3, APOC4, APOD, APOE, APOH, APOL1, APOL3, APOM, APP, APRT, APTX, AQP1, AQP2*, AQP3, AQP4, AQP5, AQP7, AR, AREL1, ARF4, ARFGEF2, ARG1, ARHGAP24, ARHGAP31, ARHGAP6, ARHGAP9, ARHGEF10, ARHGEF11, ARHGEF12, ARHGEF6, ARHGEF7, ARID1A*, ARID1B*, ARL11, ARL13B, ARL14EP, ARL6, ARL6IP5, ARMS2, ARPC3, ARSA, ARSB*, ARSE, ARSF, ART4, ARVCF, AS3MT, ASAH1, ASAH2, ASB10*, ASCC1, ASCC3, ASCL1*, ASIC3, ASIP, ASL, ASMT*, ASMTL, ASNS, ASPA, ASPM, ASPN, ASPRV1, ASS1, ASTN2*, ASXL1, ATCAY, ATF1, ATF3, ATF5, ATF6, ATG16L1, ATG7, ATIC, ATL1, ATM*, ATN1, ATP10A, ATP10D, ATP13A2, ATP13A4, ATP1A2, ATP1A3, ATP1B1, ATP2A1, ATP2A2, ATP2A3, ATP2B2, ATP2B4, ATP2C1, ATP5E, ATP5SL, ATP6AP2, ATP6V0A1, ATP6V0A2, ATP6V0A4, ATP6V1B1, ATP7A*, ATP7B, ATP8A2, ATP8B1, ATPAF2, ATR, ATRNL1, ATRX, ATXN1, ATXN10, ATXN2, ATXN3, ATXN3L, ATXN7*, AUH, AURKA, AURKC, AUTS2, AVPR1A, AVPR1B, AVPR2, AXIN1*, AXIN2*, AXL, B2M, B3GALNT1, B3GALTL, B3GAT3, B3GNT1, B3GNT3, B4GALT1*, B4GALT7, B9D1, B9D2, BAALC, BAAT*, BACE1, BAG3, BAG6, BANF1, BANK1, BAP1, BARD1, BAX, BBS1, BBS10, BBS12, BBS2, BBS4, BBS5, BBS7, BBS9, BCAM, BCAP31, BCAT1, BCAT2, BCHE, BCKDHA, BCKDHB, BCL10, BCL11A, BCL2, BCL2A1, BCL2L11, BCL2L2, BCL9, BCMO1, BCOR, BCORL1, BCR, BCS1L, BDKRB2, BEAN1, BEST1, BEX4, BFSP1*, BFSP2, BHMT, BICC1, BICD1*, BIN1, BIRC5, BLK, BLM, BLMH, BLNK, BLOC1S6, BLVRA, BMI1, BMP1, BMP10, BMP15, BMP2, BMP2K*, BMP4, BMP5, BMP7, BMPER, BMPR1A, BMPR1B, BMPR2, BNC2, BOLA3, BPGM, BPI, BPIFA1, BRAF*, BRAP, BRAT1*, BRCA1, BRCA2, BRCC3, BRD1, BRIP1, BRSK2, BRWD1, BRWD3, BSCL2, BSG, BSND, BST1, BTAF1*, BTBD9*, BTC*, BTD, BTK, BTLA, BUB1B, C10orf11*, C10orf137, C10orf2, C12orf57, C12orf65, C19orf12, C1GALT1, C1QA, C1QB*, C1QC, C1QTNF5, C1R, C1S, C2, C2orf71, C3, C4B, C5, C5AR2, C6, C6orf15, C7, C7orf10, C8A, C8B, C8orf37, C9, C9orf72, CA1, CA12, CA2, CA4, CA6, CA8, CABIN1, CABP4*, CACNA1A, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H*, CACNA1S, CACNA2D1, CACNA2D3, CACNA2D4,CACNB2, CACNB4, CACNG2, CADM1, CALCA, CALCR, CALHM1, CALM1, CALM3, CALR, CALR3, CAMK4, CAMKK1, CAMKK2, CAMP, CAMTA1, CANT1, CAPN10, CAPN13, CAPN3, CARD14, CARD8, CARD9, CARTPT, CASC5, CASK, CASP1, CASP10*, CASP12, CASP2, CASP3, CASP5, CASP8, CASP9, CASQ2, CASR, CAST, CAT, CATSPER1, CATSPER2, CATSPER3*, CATSPER4, CAV1, CAV3*, CBFB, CBL, CBLB, CBR1, CBR3, CBS, CBX2, CBX4, CC2D1A, CC2D2A, CCBE1, CCDC103, CCDC14, CCDC170, CCDC22, CCDC28B, CCDC39, CCDC40, CCDC50, CCDC8, CCDC88C, CCHCR1, CCK, CCKAR, CCKBR, CCL11, CCL13, CCL17, CCL2, CCL22, CCL26, CCL3L1, CCL5, CCL7, CCM2, CCNA2, CCND1, CCPG1, CCR1, CCR2, CCR3, CCR5, CCR6, CCR7*, CCRL2, CCT5, CD109, CD14, CD151, CD177, CD19, CD1A, CD1E, CD207, CD209, CD22, CD226, CD24*, CD244, CD247, CD27, CD2AP, CD320, CD36, CD38, CD3D*, CD3E, CD3EAP, CD3G, CD4, CD40, CD40LG, CD44, CD46, CD5, CD55, CD58, CD59, CD72, CD79A, CD79B, CD81, CD86, CD8A*, CD96, CDA, CDAN1, CDC42BPB, CDC6, CDC73, CDH1, CDH12, CDH13, CDH15, CDH23, CDH3, CDH5, CDH8, CDHR1, CDK11A, CDK4, CDK5R1, CDK5RAP2, CDK5RAP3, CDK7, CDKL3, CDKL5, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C*, CDON, CDSN, CDT1*, CEACAM16, CEBPE, CEL*, CELSR1*, CENPJ, CEP135, CEP152, CEP290, CEP41, CEP57, CEP63, CEP68, CEP85L, CER1, CERKL, CERS6, CES1, CES2, CETP, CFB, CFC1, CFC1B*, CFD, CFH, CFHR1*, CFHR2, CFHR3*, CFHR4, CFHR5, CFI, CFL2, CFLAR*, CFP, CFTR*, CGA, CGB, CHAT, CHD1L, CHD2, CHD3, CHD6, CHD7, CHD8, CHDH, CHEK2, CHFR, CHGA, CHI3L1, CHI3L2, CHIA, CHIT1, CHKB, CHL1, CHM*, CHMP2B, CHMP4B, CHN1, CHRDL1, CHRFAM7A, CHRM1, CHRM2, CHRM3, CHRNA1, CHRNA3, CHRNA5*, CHRNA7, CHRNA9, CHRNB1, CHRNB2, CHRNB4, CHRND, CHRNE, CHRNG, CHST14*, CHST3, CHST8, CHSY1*, CHUK, CIB2, CIC, CIDEA, CIDEC, CIITA, CILP, CIRH1A, CISD2, CISH, CITED2, CKM, CLCA1, CLCA2, CLCF1, CLCN1, CLCN2, CLCN5, CLCN7, CLCNKA, CLCNKB, CLDN1, CLDN14, CLDN16, CLDN19, CLEC11A*, CLEC2D, CLEC4M, CLEC7A, CLIC2, CLK2, CLMP, CLN3, CLN5*, CLN6, CLN8*, CLNK, CLOCK, CLPS, CLPTM1, CLRN1, CLSTN2, CLTCL1, CLU, CLUL1, CLYBL, CMA1, CMPK1, CNBP, CNDP1, CNGA1, CNGA3, CNGB1, CNGB3, CNKSR1, CNKSR2*, CNNM2, CNNM4, CNOT3, CNOT4, CNPY3, CNR1, CNR2*, CNTF*, CNTN1, CNTN4, CNTNAP2, CNTNAP4, CNTNAP5, COA5, COCH, COG1*, COG4, COG5, COG6, COG7, COG8, COL10A1, COL11A1, COL11A2, COL12A1, COL17A1, COL18A1, COL1A1, COL1A2, COL25A1, COL2A1, COL3A1, COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6, COL5A1, COL5A2, COL6A1, COL6A2, COL6A3, COL6A5, COL7A1, COL9A1, COL9A2, COL9A3, COLEC11, COLQ, COMMD1*, COMP, COMT, COQ2, COQ4, COQ5, COQ6, COQ9, CORIN, CORO1A, COX10, -- COX15, COX4I1, COX4I2, COX6B1, COX7A1*, COX7A2, CP, CPA4, CPA6, CPB2, CPE, CPLX2, CPN1, CPOX, CPS1, CPT1A, CPT1B, CPT2*, CPZ, CR1, CR2, CRADD, CRB1, CRBN, CREB1, CREB3L3, CREBBP, CRELD1, CRH, CRHR1, CRISP2, CRK, CRKL, CRLF1*, CRP, CRTAP*, CRX, CRYAA, CRYAB, CRYBA1, CRYBA4, CRYBB1, CRYBB2, CRYBB3, CRYGB, CRYGC, CRYGD, CRYGS, CRYM, CSAG1, CSDE1, CSF1, CSF1R, CSF2, CSF2RA, CSF2RB, CSF3R, CSGALNACT1, CSH1, CSMD1, CSMD3, CSNK1A1L, CSNK1D, CSNK1E, CSNK2A2, CSNK2A3, CSRP3, CST3, CSTA, CSTB, CSTF2T, CTC1, CTDP1*, CTGF*, CTH, CTHRC1, CTLA4, CTNNA3, CTNNB1, CTNND1, CTNS, CTRC, CTSA, CTSB, CTSC, CTSD, CTSG, CTSK, CTSZ, CTTNBP2, CUBN, CUL3, CUL4B, CUL5, CUL7, CX3CR1, CXCL10, CXCL11, CXCL12, CXCL16, CXCL5, CXCR1*, CXCR3, CXCR4, CYB5A, CYB5R3, CYBA, CYBB, CYBRD1, CYCS, CYLD*, CYP11A1, CYP11B1, CYP11B2, CYP17A1, CYP19A1, CYP1A1, CYP1A2, CYP1B1, CYP21A2, CYP24A1, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP2A13, CYP2A6, CYP2B6, CYP2C18, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2R1*, CYP2W1, CYP3A4, CYP3A43, CYP3A5, CYP3A7, CYP46A1, CYP4A11, CYP4A22, CYP4B1, CYP4F12, CYP4F2, CYP4F22, CYP4F3, CYP4V2, CYP7A1, CYP7B1, CYSLTR1, CYSLTR2, D2HGDH, DAG1, DAO, DAOA, DAPK1, DARC, DARS2, DAZL, DBH, DBI*, DBT, DCAF13, DCAF17, DCC, DCDC2, DCK, DCLK1, DCLRE1C, DCN, DCP1B, DCTD, DCTN1, DCX, DCXR, DDAH1, DDAH2, DDB2, DDC, DDOST, DDR1, DDR2, DDX11, DDX20, DDX25, DDX39B, DDX5, DDX53, DDX58, DEAF1*, DEC1, DECR1, DEFB1, DEFB126, DEFB4A, DES*, DFNA5, DFNB31, DFNB59, DGAT1*, DGCR14, DGCR2, DGCR6, DGCR8*, DGKD, DGUOK, DHCR24, DHCR7, DHDDS, DHFR, DHH*, DHODH, DHRS4L1, DHX16, DHX36, DHX37, DIABLO, DIAPH1, DIAPH2*, DIAPH3, DICER1, DIO1, DIO2, DIP2A, DIP2B, DIP2C, DIRC2, DIS3L2, DISC1, DKC1, DKK2, DKK3, DLAT, DLD, DLG3*, DLG5, DLGAP2, DLGAP3, DLL1, DLL3, DLX3*, DLX5, DLX6, DMBT1, DMC1, DMD, DMGDH, DMP1, DMPK, DMRT1, DMXL1, DNAAF1, DNAAF2, DNAAF3, DNAH11, DNAH5, DNAH9, DNAI1, DNAI2, DNAJA4*, DNAJB2, DNAJB6, DNAJC19, DNAJC5, DNAJC6, DNAL1, DNASE1, DNASE1L3, DNASE2, DND1, DNM1*, DNM1L, DNM2, DNMT1,DNMT3A, DNMT3B, DNMT3L, DOC2A, DOCK3, DOCK4, DOCK6, DOCK8, DOCK9, DOK7, DOLK, DPAGT1, DPM1, DPM3, DPP10, DPP6*, DPY19L2, DPYD, DPYS, DPYSL2, DRD1, DRD2, DRD3, DRD4*, DRD5, DROSHA, DRP2, DSC2, DSC3, DSCAM, DSG1, DSG2, DSG4, DSP, DSPP, DST, DTNA, DTNBP1, DUOX2, DUOXA2, DUSP23*, DXO, DYM, DYNC1H1, DYNC2H1, DYRK1A, DYSF, DYX1C1, EARS2, EBAG9, EBP, ECE1, ECI1, ECM1, ECM2, ECSIT, EDA, EDA2R, EDAR, EDARADD, EDN1, EDN2, EDN3, EDNRA, EDNRB, EEF1B2, EEF2K, EFCAB5, EFEMP1, EFEMP2, EFHC1, EFHC2, EFNB1, EFR3A, EFTUD2, EGF, EGFR, EGR2*, EGR3, EHD2, EHMT1, EHMT2, EIF2AK3, EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5, EIF3H, EIF4E, EIF4G1, ELAC2, ELANE, ELAVL2, ELF4*, ELK1, ELN, ELOVL4, ELP2, ELP4, EMC4, EMD*, EME1, EMG1, EMX2, EN2*, ENAM, ENG, ENO1, ENO3, ENPP1, ENSA, ENTPD1, EOMES, EP300, EPAS1, EPB41, EPB41L1, EPB42, EPC2, EPCAM, EPHA2*, EPHA3, EPHA5, EPHA7, EPHB2, EPHB6, EPHX1, EPHX2, EPM2A*, EPO, EPOR, EPX, ERAP1, ERAP2, ERBB3, ERBB4, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5*, ERCC6, ERCC8, ERLIN2, ESCO2, ESPN*, ESR1, ESRRB, ETFA, ETFB, ETFDH, ETHE1, ETNPPL, EVC*, EVC2, EXO1, EXO5*, EXOSC3, EXT1, EXT2, EXTL3*, EYA1, EYA4, EYS, EZH2*, F10, F11, F12, F13A1, F13B, F2, F2R*, F5, F7, F8, F9*, FA2H, FAAH*, FAAH2*, FABP2, FABP3*, FABP4, FABP6*, FABP7, FADD*, FAH, FAM126A, FAM134B, FAM161A, FAM205A, FAM20A, FAM20C, FAM58A*, FAM83H, FAM91A1, FANCA, FANCB*, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FARS2, FAS, FASLG, FASN, FASTKD2, FBLIM1, FBLN1, FBLN5, FBN1, FBN2, FBN3, FBP1, FBXL6*, FBXO10, FBXO18, FBXO7, FBXW11, FBXW4, FBXW7, FCAR, FCER1A, FCER2, FCGR1A*, FCGR2A, FCGR2B, FCGR3A, FCGR3B*, FCGRT, FCN2, FCN3, FCRL3, FDFT1, FECH, FEM1A*, FEN1, FERMT1, FERMT3, FEZF2, FFAR1, FFAR4, FGA, FGB, FGD1*, FGD3, FGD4, FGF1, FGF10, FGF14, FGF20, FGF23, FGF3, FGF8, FGF9, FGFBP1, FGFR1, FGFR2, FGFR3, FGFR4, FGFRL1, FGG, FH, FHL1, FHL2, FIG4, FIGLA, FIP1L1, FKBP10, FKBP14, FKBP5, FKBP6, FKBPL, FKRP*, FKTN, FLCN, FLG, FLNA, FLNB, FLNC, FLT1, FLT3, FLT4, FLVCR1*, FMN1, FMN2, FMO1, FMO2, FMO3*, FMO4, FMO5, FMR1, FN1, FN3K, FOLH1, FOLR1, FOXA1*, FOXA2*, FOXA3*, FOXD4*, FOXF1*, FOXI1, FOXN1, FOXP1, FOXP2, FOXRED1, FPGS, FPR1, FPR2, FRA10AC1, FRAS1, FREM1, FREM2, FREM3*, FRG1, FRK, FRMD6, FRMD7, FRMPD4, FRY, FRZB, FSCB, FSCN2, FSHB, FSHR, FTCD*, FTH1, FTHL17, FTL, FTO*, FTSJ1, FUCA1, FURIN, FUS, FUT1, FUT2, FUT3, FUT6*, FUT7, FUT8, FUZ, FXN, FXYD2, FXYD6, FYCO1, FZD1*, FZD3, FZD6, FZD9*, G6PC, G6PC2, G6PC3, G6PD, GAA, GAB2*, GABBR1*, GABRA1, GABRA5, GABRA6, GABRB3, GABRD*, GABRG1, GABRG2, GABRG3, GABRR2, GAD1, GAD2, GADD45B, GAK, GAL3ST3*, GALC, GALE, GALK1, GALNS*, GALNT12*, GALNT18, GALNT2*, GALNT3, GALNT9, GALNTL5, GALP, GALT, GAMT*, GAN, GAP43, GARS, GAS2L2, GAS6*, GATA1, GATA2, GATA3, GATM, GBA, GBA3, GBE1, GBGT1, GC, GCDH, GCGR, GCH1*, GCK, GCKR, GCLC, GCLM*, GCM2, GCNT2*, GDAP1, GDF15, GDF3*, GDF5*, GDF6*, GDF9*, GDI1*, GDNF, GEMIN2, GEMIN4, GFAP*, GFER*, GFI1, GFI1B, GFM1, GFPT1, GFPT2, GFRA1, GGCX, GGH, GGT5, GH1, GH2, GHR, GHRH, GHRHR, GHRL, GHSR, GIF, GIGYF2, GIMAP8, GIP, GIPC3*, GIPR, GIT1, GJA1, GJA3*, GJA4, GJA5*, GJA8, GJB1, GJB2*, GJB3, GJB4*, GJB6, GJC3, GJD2, GK, GLA, GLB1, GLCCI1*, GLDC, GLE1, GLI1, GLI2*, GLI3, GLIS2*, GLIS3*, GLMN, GLO1, GLP1R, GLRA1, GLRB, GLS, GLTSCR1, GLUD1, GLUD2, GLUL, GLYCTK, GM2A, GMIP, GNA14, GNAI2*, GNAS, GNAT1, GNAT2, GNB1L, GNB3, GNB5, GNE, GNMT, GNPAT, GNPTAB, GNPTG, GNRH1, GNRHR, GNS, GOLGA3, GOLGA5, GON4L, GORAB, GOSR2, GOT1, GP1BA*, GP2, GP6, GP9, GPAM, GPANK1, GPATCH8, GPBAR1, GPC3, GPC4, GPC6, GPD1, GPD1L, GPD2, GPHN, GPI, GPIHBP1, GPR139*, GPR179*, GPR55*, GPR56, GPR98, GPS1, GPSM2, GPT, GPX1, GPX4*, GRB10, GREM1, GRHL2, GRHPR, GRIA3, GRID1, GRIK1, GRIK2, GRIK3, GRIK4, GRIN1, GRIN2A, GRIN2B*, GRIN3A, GRIP1, GRK1, GRK4, GRK5, GRM1, GRM3, GRM6, GRM7, GRM8, GRN, GRPR*, GRXCR1, GSC*, GSDMA, GSDMB, GSE1, GSK3B*, GSN*, GSPT1, GSPT2, GSR, GSS, GSTA1, GSTA2, GSTA3, GSTK1, GSTM3, GSTM4, GSTO1, GSTO2, GSTP1, GSTT2, GSTZ1, GTF2E1, GTF2H1, GTF2H5, GTF2IRD1, GTF2IRD2, GUCA1A, GUCA1B, GUCY2C, GUCY2D, GUSB, GYG1, GYLTL1B*, GYPA, GYPB, GYPC, GYPE, GYS1, GYS2, GZMB, H2BFWT, H6PD, HABP2, HACE1, HADH, HADHA, HADHB, HAL, HAMP, HAND1, HARS, HARS2, HAS1, HAVCR1, HAX1, HBA1, HBA2, HBB, HBD, HBE1, HBG1, HBG2, HBM, HBS1L, HBZ, HCCS, HCK, HCLS1, HCN1, HCRT*, HCRTR1, HCRTR2, HDAC4, HDAC8, HDAC9, HDC, HDLBP, HDX, HELQ, HEPACAM, HERC2, HES6*, HES7*, HESX1, HEXA, HEXB, HEY1, HFE, HFE2, HGD, HGF, HGSNAT*, HHEX, HHIP, HIBCH, HIF1A, HIF1AN, HIGD2A, HIP1, HIST1H2AE, HIST3H3, HK1, HK2, HLA--A, HLA--B, HLA-- C, HLA--DMB, HLA--DOA, HLA--DPB1, HLA--DQA1*, HLA--DQB1, HLA--DRA, HLA--DRB1, HLA--DRB5*, HLA--E, HLA--G, HLCS,HLX*, HMBS, HMCN1, HMGA1, HMGA2, HMGCL, HMGCR, HMGCS2*, HMHA1, HMOX1, HMOX2*, HMSD, HMX2, HNF1A, HNF1B, HNF4A, HNMT, HNRNPH3, HNRNPU, HOGA1, HOMER2, HOXA1*, HOXA10*, HOXA11, HOXA2, HOXB6, HOXD10, HOXD13*, HOXD4*, HP*, HPD, HPGD, HPRT1*, HPS1*, HPS3, HPS4, HPS5, HPS6, HPSE2, HR*, HRAS, HRC*, HRG, HRH2, HRH3, HS1BP3, HSD11B1, HSD11B2*, HSD17B1, HSD17B10, HSD17B2, HSD17B3, HSD17B4, HSD3B1*, HSD3B2*, HSD3B7, HSF4, HSP90AA1, HSP90B1, HSPA1A*, HSPA1B*, HSPA1L*, HSPA5, HSPA8, HSPA9, HSPB1, HSPB3, HSPB6, HSPB7, HSPB8*, HSPD1, HSPG2, HTN3, HTR1A, HTR1B, HTR2A, HTR2B, HTR2C, HTR3A, HTR3B, HTR3C, HTR3E, HTR5A, HTR6, HTR7, HTRA1*, HTRA2, HTT, HUS1B, HUWE1, HVCN1, HYDIN, HYLS1, IAPP, ICAM1, ICAM4, ICAM5*, ICK, ICOS*, ID3, IDE, IDH1, IDH2*, IDH3B, IDO1, IDS*, IDUA*, IER3IP1, IFI30, IFI44L, IFIH1, IFITM3, IFITM5, IFNA10, IFNA17, IFNA2, IFNAR1, IFNAR2, IFNG, IFNGR1, IFNGR2*, IFNL3, IFRD1, IFT122, IFT140, IFT43, IFT80, IGBP1, IGF1, IGF1R, IGF2, IGF2R*, IGFALS, IGFBP1, IGFBP3, IGFBP5, IGFBP7*, IGHMBP2, IGLL1, IHH, IKBIP, IKBKAP, IKBKG, IL10, IL10RA, IL10RB, IL11RA, IL12A, IL12B, IL12RB1*, IL12RB2, IL13, IL16, IL17A, IL17F, IL17RA, IL17RB, IL17REL, IL18, IL18R1, IL18RAP, IL19*, IL1A, IL1B, IL1R1, IL1RAPL1, IL1RL1, IL1RN, IL2, IL20RA, IL20RB, IL21, IL21R, IL23R, IL2RA, IL2RG, IL3, IL31RA, IL36RN, IL4, IL4R, IL5, IL6, IL6R, IL7, IL7R*, IL8, IL9, IL9R, ILDR1, ILK, IMMP2L, IMMT, IMPA2*, IMPAD1, IMPDH1, IMPDH2, IMPG2, INF2*, INHA*, INMT, INPP4A, INPP5E*, INS, INSIG1, INSIG2, INSL3*, INSL6*, INSR, INVS, IQCB1, IQGAP1, IQGAP2, IQGAP3, IQSEC2*, IRAK1, IRAK3*, IRAK4, IRF1, IRF2, IRF4*, IRF5, IRF6, IRF7, IRF8, IRGM, IRS1*, IRS4, IRX4*, IRX5, ISCU, ISL1, ISPD, ISYNA1, ITCH, ITGA11, ITGA2, ITGA2B, ITGA3, ITGA4, ITGA6, ITGA7, ITGA9, ITGAE, ITGAM, ITGB2, ITGB3*, ITGB4, ITIH1, ITIH3, ITIH4, ITIH6, ITK, ITM2B, ITPA*, ITPKC*, ITPR1, ITPR3, ITSN2, IVD, IYD, JAG1, JAG2, JAK2, JAK3, JAM3, JMJD1C, JPH3, JRK, JUN, JUP, KAL1, KALRN, KANK1, KANSL1, KARS, KAT6B, KATNAL2, KBTBD13*, KCNA1, KCNA3*, KCNA5, KCNAB2, KCND2, KCND3*, KCNE1, KCNE2*, KCNE3, KCNE4, KCNH2, KCNIP4, KCNJ1, KCNJ10, KCNJ11, KCNJ13*, KCNJ15, KCNJ18*, KCNJ2, KCNJ3, KCNJ5, KCNJ6, KCNJ8, KCNJ9*, KCNK18, KCNK6*, KCNK9, KCNMA1, KCNMB1, KCNMB3, KCNN3, KCNQ1*, KCNQ2, KCNQ3, KCNQ4*, KCNS1*, KCNS3, KCNV2, KCTD13, KCTD7, KDM4C, KDM5A, KDM5C, KDM6A, KDM6B, KDR, KEL, KERA*, KHDC3L, KHK, KIAA0100, KIAA0196, KIAA0226, KIAA0232, KIAA0319, KIAA0513, KIAA1033, KIAA1199, KIAA1279*, KIAA1377, KIAA1432, KIAA1462*, KIAA2022, KIF11, KIF17, KIF18A, KIF1A, KIF1B, KIF21A, KIF22, KIF5A, KIF5B, KIF6, KIF7*, KIFAP3, KIR2DL1, KIR2DL3*, KIR2DL4*, KIR3DL1*, KIR3DL2, KIRREL3, KISS1, KISS1R, KIT, KITLG, KL*, KLB, KLF1, KLF10, KLF11*, KLF5*, KLF6, KLF7, KLHDC8B, KLHL10, KLHL3, KLHL7, KLHL9, KLK1, KLK12, KLK15, KLK3, KLK4, KLK7, KLKB1, KLRK1, KMT2C, KMT2D*, KMT2E, KNG1, KPNA1, KRAS, KRIT1, KRT1, KRT10, KRT12*, KRT13*, KRT14, KRT16, KRT17, KRT18, KRT2, KRT3, KRT31, KRT37, KRT38, KRT4, KRT5*, KRT6A, KRT6B, KRT6C, KRT74, KRT75, KRT8, KRT81, KRT83, KRT85, KRT86, KRT9, KRTAP1--1, KYNU, L1CAM, L2HGDH, L3MBTL1, LAMA1, LAMA2, LAMA3, LAMA4, LAMA5, LAMB1, LAMB2, LAMB3, LAMC1, LAMC2, LAMC3, LAMP2, LAMTOR2, LARGE, LARS2, LBP, LBR, LCA5, LCAT, LCE5A, LCN10, LCT, LDB3*, LDHA, LDHB, LDLR, LDLRAD4, LDLRAP1*, LEFTY2, LEP, LEPR, LEPRE1, LEPREL1, LETM1, LGALS13, LGALS2, LGALS3, LGI1, LHB, LHCGR, LHFPL5, LHX1*, LHX3*, LHX4*, LHX8, LIAS, LIF, LIFR, LIG1, LIG3, LIG4, LILRA3, LIM2, LIMK1, LIN28A, LIN28B, LINS*, LIPA, LIPC, LIPE, LIPG, LIPH, LIPI, LIPN, LITAF, LLGL1, LMAN1, LMBR1, LMBRD1, LMF1, LMNA, LMNB1, LMNB2, LMX1B, LNX2, LOX, LOXHD1, LOXL1, LOXL2, LPAR1, LPAR6*, LPIN1, LPIN2, LPIN3, LPL, LPP, LRAT, LRCH1, LRFN5, LRP1, LRP2, LRP4, LRP5, LRP6, LRP8, LRPAP1, LRPPRC, LRRC4, LRRC6, LRRC8A, LRRK2, LRSAM1, LRTOMT, LTA, LTBP1, LTBP2, LTBP3, LTBP4, LTC4S*, LTF, LTK, LTN1, LUM, LY96, LYN, LYST, LYZ, LZTFL1, LZTS1, MACROD2, MAD1L1, MAD2L1, MADD, MAFB, MAGEE2, MAGI2*, MAGT1, MAK, MAMLD1*, MAN1A2, MAN1B1, MAN2B1, MANBA, MAOA, MAOB, MAP2, MAP2K1, MAP2K2, MAP2K3, MAP2K4*, MAP3K1*, MAP3K15*, MAP4K5, MAP6*, MAP7D3, MAPK10, MAPK8IP1, MAPT, MARS2, MASP1, MASP2, MAST4, MASTL, MAT1A, MATR3*, MAVS, MAX, MBD1, MBD3, MBD4, MBD5, MBL2, MBTPS2, MC1R, MC2R, MC3R, MC4R, MCCC1, MCCC2, MCEE, MCF2L2, MCFD2, MCHR1*, MCL1*, MCM3AP, MCM4, MCM5, MCM6, MCOLN1, MCPH1, MDH1, MDM2, MDM4, MDN1, MECP2, MED12, MED13, MED13L, MED17, MED23, MED25, MEF2A, MEF2C, MEFV, MEGF10, MEGF11, MEIS1, MEIS2, MEN1, MEP1B, MERTK, MESDC2, MESP2*, MEST, MET, MFF, MFGE8, MFI2, MFN2, MFRP, MFSD2A, MFSD8, MGAT1, MGAT2*, MGAT4C, MGEA5, MGLL, MGMT, MGP, MGST2, MGST3, MIA3, MICA, MICB, MID1*, MIF, MIIP, MINPP1, MIP, MIPOL1, MITF, MKKS, MKL1, MKRN3, MKS1, MLC1, MLH1, MLH3, MLLT3, MLPH, MLYCD*, MMAA, MMAB, MMACHC*, MMADHC, MME, MMEL1, MMP1, MMP10, MMP12, MMP13, MMP14, MMP2, MMP20, MMP3, MMP7, MMP8, MMP9, MOCOS, MOCS1, MOCS2, MOG, MOGS, MOK, MPDU1, MPDZ, MPG, MPHOSPH8, MPI, MPL, MPLKIP, MPO, MPP3, MPP4, MPP6, MPP7, MPST*, MPV17, MPZ, MR1, MRAP, MRC1, MRE11A, MRPL3, MRPL48, MRPS16, MRPS22, MRRF, MS4A1, MS4A12, MS4A2, MS4A3, MS4A6A, MS4A6E, MSH2, MSH3, MSH4, MSH5, MSH6*, MSMB, MSMO1, MSR1, MSRB3, MST1, MST1R, MSTN, MSX1*, MSX2, MT1A, MT2A, MTAP, MTCH2, MTFMT, MTHFD1, MTHFD1L*, MTHFR, MTHFS, MTM1, MTMR14, MTMR2, MTMR9, MTNR1A, MTNR1B, MTO1, MTPAP, MTR, MTRR, MTTP, MTUS1, MUC1*, MUC13, MUC2, MUC4, MUC5B, MUC6, MURC*, MUSK*, MUT, MUTYH, MVK, MX1, MYB, MYBL2, MYBPC1, MYBPC3, MYC, MYCL, MYD88, MYF6, MYH11, MYH13, MYH14, MYH15, MYH2, MYH3, MYH6, MYH7, MYH8, MYH9, MYL2, MYL3, MYLIP, MYLK, MYLK2, MYO15A, MYO18B, MYO1A, MYO1C, MYO1E, MYO1F, MYO3A, MYO5A, MYO5B, MYO6, MYO7A, MYO7B, MYO9B, MYOC*, MYOCD, MYOM1, MYOT, MYOZ2, MYPN, MYT1, MYT1L, NAA10, NAGA, NAGLU*, NAGPA*, NAGS*, NAIP, NAMPT, NAPRT1, NARS2, NAT1, NAT2, NAV2, NBAS, NBEA, NBEAL2, NBN, NBPF1, NCALD, NCAM1, NCAN, NCAPD2, NCF1, NCF2, NCF4, NCKAP1, NCOA1, NCOA3, NCR3, NCS1, NCSTN, NDE1, NDN, NDOR1, NDP, NDRG1, NDST1, NDUFA1, NDUFA10, NDUFA11*, NDUFA12, NDUFA13, NDUFA2, NDUFA4, NDUFA6, NDUFA7, NDUFA8, NDUFA9, NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF5, NDUFAF6, NDUFAF7, NDUFB1, NDUFB3, NDUFB6, NDUFB9, NDUFC2, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS5, NDUFS6*, NDUFS7, NDUFS8, NDUFV1, NDUFV2, NDUFV3, NEB, NEBL, NEDD4L, NEDD9, NEFH*, NEFL, NEFM, NEGR1, NEIL1, NEIL2*, NEK1, NEK8, NELFA, NELL1, NEU1, NEU2, NEUROD1, NEUROG3*, NEXN, NF1, NF2, NFATC4, NFE2L2, NFIA, NFIX, NFKB1, NFKBIA, NFKBIL1, NFU1, NGF, NGFR, NHEJ1, NHLRC1, NHP2, NHS*, NID1, NINJ1, NIPA1*, NIPAL4, NIPBL, NIPSNAP1, NIPSNAP3A, NKAIN2, NKX2--1*, NKX2--5*, NKX2--6*, NKX3--1, NKX3--2*, NLGN1, NLGN2, NLGN3*, NLGN4X, NLRP1, NLRP14, NLRP2, NLRP3, NLRP7, NLRX1, NMB, NME1, NME8, NMNAT1, NMT2, NMU, NOBOX*, NOD1, NOD2, NODAL, NOG*, NOP10, NOP56, NOS1, NOS1AP, NOS2, NOS3, NOTCH1, NOTCH2, NOTCH3*, NOTCH4, NPAP1, NPAS2, NPAS3, NPAT, NPC1, NPC1L1, NPC2, NPFFR2, NPHP1, NPHP3, NPHP4, NPHS1, NPHS2, NPL, NPM1, NPPA, NPPB, NPPC*, NPR1, NPR2*, NPR3, NPSR1, NPTN, NPY, NPY1R, NPY2R, NQO1, NQO2, NR0B1, NR0B2*, NR1H2, NR1H3, NR1H4, NR1I2, NR1I3, NR2E1, NR2E3, NR2F1*, NR3C1, NR3C2, NR4A2, NR5A1, NRAS, NRG1*, NRG3*, NRIP1, NRL, NRP2, NRXN1*, NRXN2*, NRXN3, NSD1, NSDHL, NSMF, NSUN2, NSUN7, NT5C1B, NT5C3A, NT5E, NTF3, NTHL1, NTNG1, NTRK1, NTRK2, NTRK3, NUAK1, NUBPL, NUDC, NUDT1, NUDT6, NUMBL, NUP155, NXF3, NXF5, NXNL1, OAS1*, OAS2, OAT, OAZ1, OBSCN, OBSL1, OCA2, OCRL, ODC1, OFD1*, OGG1, OLFM2*, OLR1, OMG, OPA1, OPA3, OPHN1*, OPN1LW, OPN1MW, OPN1SW, OPTC, OPTN, ORAI1*, ORC1, ORC4, ORC6, OSMR, OSTM1, OTC, OTOA, OTOF, OTX2, OXCT1, P2RX1, P2RX5, P2RY11, P2RY12*, P2RY4, PABPC4L, PABPN1*, PACRG, PAFAH1B1, PAFAH1B3, PAH, PAK3, PAK7, PALB2, PALLD, PANK2*, PAPD7, PAPSS2, PARD3B, PARD6A, PARK2, PARK7, PARL, PARP1, PARP2, PASK, PAWR*, PAX1*, PAX2, PAX3, PAX4, PAX5, PAX6, PAX7, PAX8, PAX9, PC, PCBD1, PCCA, PCCB, PCDH11X, PCDH15, PCDH18, PCDH19, PCDH9, PCDHA10*, PCDHA13, PCDHB4, PCK1, PCK2, PCM1, PCMT1, PCNT, PCOLCE, PCSK1, PCSK2, PCSK9, PDCD1, PDCD10, PDCD5, PDE10A, PDE11A, PDE4B, PDE4D, PDE6A, PDE6B, PDE6C, PDE6G, PDE6H, PDE7B, PDE8B, PDGFB, PDGFC, PDGFRA, PDHA1, PDHB, PDHX*, PDLIM3, PDLIM5, PDP1, PDPK1, PDSS1*, PDSS2, PDX1*, PDXK, PDYN, PDZD7, PEAR1, PECAM1, PECR, PEMT, PENK, PEPD, PER1, PER2, PER3, PEX1*, PEX10*, PEX11B, PEX12, PEX13, PEX14, PEX16, PEX19, PEX2, PEX26*, PEX3, PEX5, PEX6*, PEX7, PFAS, PFKM, PFN1, PGAM1, PGAM2, PGBD1, PGC, PGD, PGK1, PGM1, PGR, PGRMC1, PHB, PHEX, PHF11, PHF2, PHF3, PHF6, PHF8, PHGDH, PHIP, PHKA1, PHKA2, PHKB, PHKG2, PHLDA2*, PHLPP2, PHOX2B*, PHYH, PI3, PICALM, PICK1, PIEZO2, PIF1*, PIGA, PIGL, PIGN, PIGO, PIGR, PIGV, PIK3C2G, PIK3C3, PIK3CA*, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2*, PIK3R4, PIK3R5, PIKFYVE, PIN1, PINK1*, PIP4K2A, PIP5K1B, PIP5K1C, PITPNM3, PITX1*, PITX2*, PITX3*, PIWIL3, PKD1, PKD1L1, PKD2*, PKHD1, PKLR, PKM, PKN3, PKP1, PKP2, PLA2G10, PLA2G2A, PLA2G2D, PLA2G4A, PLA2G4C, PLA2G5, PLA2G6, PLA2G7, PLAGL1*, PLAT, PLAU, PLAUR, PLCB1, PLCB4, PLCD1, PLCE1, PLCG2, PLCZ1, PLD2, PLEC, PLEKHG4, PLEKHG5, PLEKHM1, PLG, PLIN1, PLIN4, PLN, PLOD1, PLOD2, PLOD3, PLP1, PLP2, PLTP, PLXND1*, PMAIP1, PML, PMM2, PMP22, PMS1, PMS2, PNKD, PNKP, PNMT, PNP, PNPLA1,PNPLA2, PNPLA3, PNPLA6, PNPO, POF1B, POGZ, POLB, POLD1, POLE2, POLG, POLG2, POLH, POLL, POLR1C, POLR1D, POLR2E, POLR2M, POLR3A, POLR3B, POLRMT*, POMC, POMGNT1, POMGNT2, POMP, POMT1, POMT2, PON1, PON2, PON3, POP1, POR, PORCN, POU1F1, POU3F4, POU4F3, POU5F1*, POU5F1B, POU6F2, PPARA, PPARD, PPARG*, PPARGC1A, PPARGC1B, PPAT, PPIA, PPIB, PPIG, PPM1D, PPOX, PPP1R1A*, PPP1R3A, PPP1R3C, PPP2R1A, PPP2R1B, PPP2R2B, PPP2R2C, PPT1, PQBP1, PRB1, PRB3, PRB4, PRCD, PRCP, PRDM2, PRDM5, PRDM9*, PREPL, PRF1*, PRG4, PRICKLE1*, PRICKLE2, PRKAA2, PRKACA, PRKAG2, PRKAG3, PRKAR1A, PRKCB, PRKCG, PRKCH*, PRKCSH, PRKD3, PRKDC, PRKRA, PRL, PRLHR, PRLR, PRM1, PRM2, PRMT10, PRMT3, PRMT7, PRND, PROC, PROCR, PRODH, PROK1, PROKR2, PROM1, PROP1*, PROS1, PROZ*, PRPF3, PRPF31, PRPF6, PRPF8, PRPH*, PRPH2, PRPS1, PRRC2A, PRRT2, PRRX1, PRSS1, PRSS12, PRSS56, PRSS8, PRX*, PSAP, PSAT1, PSCA, PSEN1, PSEN2, PSENEN, PSMA6, PSMB8, PSMB9, PSMC3IP, PSMD7, PSPH, PSPN*, PSTPIP1, PTAFR, PTCD1*, PTCH1, PTCH2, PTCHD1, PTCHD3, PTEN, PTGDR, PTGDR2, PTGDS, PTGER2, PTGER4, PTGES2*, PTGIR, PTGIS, PTGS1, PTGS2, PTH, PTH1R, PTHLH*, PTK7, PTPN1, PTPN11*, PTPN13, PTPN14*, PTPN2, PTPN21, PTPN22, PTPN6, PTPRB, PTPRC, PTPRCAP, PTPRD, PTPRF, PTPRJ, PTPRK, PTPRO, PTPRQ, PTPRT, PTRF, PTS, PUS1, PVR, PVRL1, PVRL3, PVRL4, PXDN, PYCR1, PYCRL*, PYGL, PYGM, PYY, PZP, QDPR, QKI, RAB11FIP5, RAB18, RAB23, RAB27A, RAB28, RAB2A, RAB39B*, RAB3GAP1, RAB3GAP2, RAB40AL, RAB7A, RAB7L1, RABGGTA, RABL6, RAC1*, RAC2, RAD21, RAD21L1, RAD23B, RAD50, RAD51*, RAD51C, RAD51D, RAD52, RAD54B, RAD54L, RAD9A, RAET1L, RAF1, RAG1, RAG2, RAI1, RALGAPA1, RALGDS, RANBP2, RANGRF, RAPSN, RARS2, RASA1, RASGRP2, RASSF1, RAX*, RB1*, RB1CC1, RBBP8, RBFOX1, RBM10, RBM15*, RBM20, RBM28, RBM8A, RBP3, RBP4, RCAN1*, RD3, RDH12, RDH5, RDX, RECQL4, REEP1, RELN, REN, RET, RETN, REV3L, RFC2, RFT1, RFWD2, RFX2, RFX5, RFX6, RFX8, RFXANK, RGMA, RGR, RGS2, RGS6, RGS7, RGS9, RGS9BP*, RHAG, RHBDF2, RHCE*, RHD*, RHO, RHOB, RHOG, RHPN2, RIMS1, RIMS3, RIN2, RIPK3, RIPK4, RLBP1, RMI1, RNASE3, RNASEH2A, RNASEH2B*, RNASEH2C, RNASEL, RNASET2, RNF113A, RNF114, RNF135*, RNF139, RNF168*, RNF170, RNF213, RNLS, ROBO1, ROBO2, ROBO3, ROCK1, ROCK2, ROGDI, ROM1, ROPN1L, ROR2, RORA, ROS1, RP1, RP1L1*, RP2, RP9, RPA1, RPA4, RPE65, RPGR*, RPGRIP1, RPGRIP1L, RPH3AL, RPIA, RPL10, RPL11, RPL21, RPL35A, RPL36, RPL5, RPN2, RPS10, RPS15, RPS17, RPS19, RPS24*, RPS26, RPS27A, RPS3, RPS6KA3, RPS6KB1, RPS6KL1, RPS7, RPTOR, RRH, RRM1, RRM2B, RRP1B, RS1, RSPH4A, RSPH9, RSPO1, RSPO4, RSRC1, RTN2, RTN4R*, RUNX1, RUNX2*, RUNX3, RUVBL1, RXFP2, RXRG, RYK*, RYR1, RYR2, RYR3, S100A14, S100B, S1PR1, SAA1, SAA2, SACS, SAG, SAGE1, SALL1, SAMD9, SAMHD1, SAR1B, SARDH, SARS2, SART1, SART3, SAT1, SATB2, SATL1, SBDS, SBF2, SBK3, SBNO1, SC5D, SCAP, SCARB1, SCARB2, SCG2, SCG3, SCGB1A1, SCGB1D2, SCGB3A2, SCN10A, SCN1A, SCN1B, SCN2A, SCN2B, SCN3A, SCN3B, SCN4A, SCN4B, SCN5A*, SCN8A, SCN9A, SCNN1A, SCNN1B, SCNN1G, SCO1, SCO2, SCP2, SCRIB, SCUBE2, SDC3*, SDCCAG8, SDHA, SDHAF1*, SDHAF2, SDHB, SDHC, SEC23A, SEC23B, SEC63, SECISBP2, SEL1L, SELE, SELL, SELP, SELPLG, SEMA3A, SEMA3E, SEMA4A, SEMA4C, SEMA4G, SEMA6D, SEMG1, SEPN1*, SEPP1, SEPSECS, SEPT9, SEPT12, SEP15, SERPINA1, SERPINA10, SERPINA3, SERPINA6, SERPINA7, SERPINB11, SERPINB3, SERPINB5, SERPINB6, SERPINC1*, SERPIND1, SERPINE1, SERPINF1, SERPINF2, SERPING1, SERPINH1, SERPINI1, SERPINI2, SERTAD1, SESN2, SETD2, SETD8*, SETDB2, SETX, SEZ6, SEZ6L2, SF3B4, SFTPA1*, SFTPA2*, SFTPB, SFTPC, SFTPD, SGCA, SGCB, SGCD, SGCE*, SGCG, SGK1, SGK223, SGSH*, SH2B1, SH2B3, SH2D1A, SH3BP2*, SH3GL1, SH3PXD2B, SH3TC2, SHANK2, SHBG, SHFM1, SHH*, SHMT1, SHOC2, SHOX, SHROOM3, SHROOM4, SI, SIAE, SIGLEC12, SIGLEC14*, SIGMAR1, SIL1, SIM1, SIPA1*, SIRT1*, SIRT3, SIRT5, SIX1*, SIX2, SIX3*, SIX6, SKI*, SKIV2L, SLC10A1, SLC10A2, SLC11A1, SLC11A2, SLC12A1, SLC12A3, SLC12A6, SLC13A2, SLC14A1, SLC14A2, SLC15A1, SLC16A1*, SLC16A12, SLC16A2, SLC16A3, SLC17A1, SLC17A3, SLC17A5, SLC17A8, SLC18A1, SLC19A1, SLC19A2, SLC19A3, SLC1A1, SLC1A2, SLC1A3, SLC20A2*, SLC22A1, SLC22A11, SLC22A12, SLC22A14, SLC22A2, SLC22A3, SLC22A4, SLC22A5, SLC22A6, SLC22A9, SLC23A1, SLC24A2*, SLC24A5, SLC25A12, SLC25A13, SLC25A15, SLC25A19, SLC25A20, SLC25A22, SLC25A3, SLC25A38, SLC25A39, SLC25A4, SLC26A1, SLC26A10, SLC26A2, SLC26A3, SLC26A4, SLC26A5, SLC26A6, SLC26A9, SLC27A4, SLC27A5, SLC28A1, SLC28A2, SLC28A3, SLC29A1, SLC29A2, SLC29A4, SLC2A1, SLC2A10, SLC2A2, SLC2A4, SLC2A9, SLC30A10, SLC30A2, SLC30A5, SLC30A8, SLC31A1, SLC33A1, SLC34A1, SLC34A2, SLC34A3, SLC35A1, SLC35C1, SLC35D1, SLC35G2, SLC36A2, SLC37A4, SLC39A13, SLC39A4, SLC3A1,SLC40A1*, SLC41A1, SLC44A2, SLC45A2, SLC46A1, SLC47A1, SLC47A2, SLC4A1, SLC4A10, SLC4A11, SLC4A3, SLC4A4, SLC52A3, SLC5A1, SLC5A11, SLC5A2, SLC5A5, SLC5A7, SLC6A1, SLC6A11, SLC6A12, SLC6A13, SLC6A14, SLC6A18, SLC6A19, SLC6A2, SLC6A20, SLC6A3, SLC6A4, SLC6A5, SLC6A8*, SLC7A1, SLC7A10, SLC7A2, SLC7A5, SLC7A7, SLC7A9, SLC8A1, SLC9A3R1, SLC9A6, SLC9A9, SLCO1A2, SLCO1B1, SLCO1B3, SLCO1C1, SLCO2A1, SLCO2B1, SLFN5, SLIT3, SLITRK1, SLURP1, SLX4, SMAD1, SMAD2, SMAD3, SMAD7*, SMAD9, SMARCA2, SMARCA4, SMARCAD1, SMARCAL1, SMARCB1, SMARCE1, SMC1A, SMC1B, SMC3, SMG1, SMG6, SMN1, SMN2, SMNDC1, SMOC1, SMOC2, SMPD1, SMPX, SMS, SMUG1, SMYD3, SNAI2*, SNAP29, SNAPC4, SNAPC5, SNCA, SNCAIP, SNCB, SNIP1, SNRK, SNRNP200, SNRPN, SNTA1*, SNTG2, SNURF, SNX10, SNX19, SNX3, SOBP*, SOCS1, SOD1, SOD2, SOHLH1, SORBS1, SORCS1*, SORL1, SORT1*, SOS1, SOST, SOX10, SOX17, SOX2, SOX5, SOX6, SOX8*, SOX9, SP100, SP110, SP7*, SPAG16, SPAG17, SPANXN5, SPAST, SPATA13, SPATA16, SPATA21, SPATA31C1, SPATA7, SPECC1L, SPG11, SPG20, SPG21, SPG7, SPI1, SPINK1, SPINK5, SPINT2*, SPP1, SPR, SPRN*, SPRR3*, SPRY2, SPRY3, SPTA1, SPTAN1, SPTB, SPTBN2, SPTBN5, SPTLC1, SPTLC2, SQSTM1, SRC, SRCAP, SRD5A2, SRD5A3, SREBF1, SREBF2, SREK1, SRGAP2, SRGAP3, SRI, SRP72, SRPX*, SRPX2, SRR, SSH1, SST, SSTR2, SSTR5*, SSX7, ST14, ST3GAL3, ST3GAL5*, ST5, ST7, ST8SIA2, STAR, STAT1, STAT3, STAT5B, STAT6, STEAP3, STEAP4, STH, STIL, STIM1, STK10, STK11, STK19, STK3, STK32A, STK33, STK39*, STK4, STMN1, STOX1*, STRA6, STRADA, STRC, STS, STX11, STX16, STX1A, STXBP1, STXBP2, STXBP5, SUCLA2, SUCLG1, SUFU, SULF1, SULT1A1, SULT1A3, SULT1C2, SULT1E1, SULT2A1, SULT2B1, SULT4A1, SUMF1, SUMO1, SUMO4, SUN2, SUOX, SUPT16H, SURF1*, SUV420H1, SV2B, SYCP3, SYN3, SYNE1, SYNE2, SYNGAP1, SYNGR1, SYNM, SYNPO, SYP, SYT11, SYT14, SYT2, SYTL3, SYTL5, T, TAAR6, TAAR9, TAB2*, TAC3, TACO1*, TACR3*, TACSTD2*, TAF1, TAF15, TAF1C, TAF1L, TAF2, TAF7L, TALDO1, TAP1, TAP2, TAPBP, TARDBP, TAS1R1, TAS1R2, TAS1R3, TAS2R16, TAS2R19, TAS2R3, TAS2R38*, TAS2R43, TAS2R46, TAS2R50, TAS2R9, TAT, TAZ, TBC1D1, TBC1D23, TBC1D24, TBC1D4, TBCE, TBK1, TBL1X, TBL1XR1, TBP, TBX10, TBX15, TBX19, TBX2*, TBX20, TBX21*, TBX22, TBX3*, TBX4*, TBX5, TBX6, TBXA2R, TBXAS1, TCAP, TCF21, TCF4, TCF7L1, TCF7L2, TCIRG1, TCN1, TCN2, TCOF1, TCP1, TCTE1, TCTE3, TCTN1, TCTN2, TDGF1, TDO2, TDP1, TDRD7, TEAD1, TECR, TECTA, TEK, TEKT2, TENM4, TEP1, TERT, TET1, TEX14, TF, TFAM, TFAP2A, TFAP2B, TFB1M, TFCP2, TFF1, TFPI, TFR2, TFRC, TG, TGFB1*, TGFB2, TGFB3, TGFBI, TGFBR1*, TGFBR2*, TGFBR3, TGFBRAP1, TGIF1, TGM1, TGM2, TGM5, TGM6, TH, THADA, THAP1, THBD*, THBS1, THBS2, THBS4, THPO*, THRA, THRB, THSD7A, TICAM1, TIMM44, TIMM8A, TIMP1, TIMP3, TINAG, TINF2, TIRAP, TJP2, TK2, TLK1, TLL1, TLR1, TLR10, TLR2, TLR3, TLR4, TLR5*, TLR6, TLR7, TLR8, TLR9*, TM4SF19, TMC1, TMC6, TMC8*, TMCO1, TMEM114, TMEM126A, TMEM127, TMEM135, TMEM138, TMEM165, TMEM173, TMEM185A, TMEM187, TMEM2, TMEM216, TMEM237, TMEM39A, TMEM43, TMEM67, TMEM70, TMEM8A*, TMEM9, TMIE, TMLHE, TMPO, TMPRSS11A, TMPRSS15, TMPRSS3, TMPRSS4, TMPRSS5, TMPRSS6, TNC, TNF, TNFAIP2*, TNFAIP3, TNFRSF10A, TNFRSF10B, TNFRSF11A*, TNFRSF11B*, TNFRSF13B, TNFRSF1A, TNFRSF1B, TNFRSF25, TNFSF10, TNFSF11, TNFSF13B, TNFSF14, TNFSF15, TNFSF4, TNFSF8, TNKS, TNNC1, TNNI2, TNNI3, TNNI3K, TNNT1, TNNT2, TNNT3, TNP1, TNR, TNS3, TNXB, TOMM40, TOP1MT, TOPBP1, TOPORS, TOR1A, TOX3, TP53*, TP53AIP1, TP53BP1, TP53I3, TP53RK*, TP63, TP73, TPCN2, TPH1, TPH2, TPI1, TPK1, TPM1, TPM2, TPM3, TPMT, TPO, TPP1, TPP2, TPSB2, TPTE, TRADD, TRAF3, TRAF3IP1*, TRAF3IP2, TRAF6, TRAK2, TRAPPC10, TRAPPC2, TRAPPC9, TRDN, TREM2, TRERF1, TREX1*, TRHR*, TRIB1, TRIB3, TRIL, TRIM17, TRIM21, TRIM22, TRIM32, TRIM37, TRIM5, TRIO, TRIOBP*, TRIP11, TRIP12, TRMT1, TRMU, TROAP, TROVE2, TRPA1, TRPC3, TRPC4, TRPC5, TRPC6, TRPM1, TRPM2, TRPM3, TRPM4, TRPM6, TRPM7, TRPS1, TRPV1, TRPV3, TRPV4, TRPV5, TRRAP, TSC1, TSC2, TSEN2, TSEN34, TSEN54*, TSFM*, TSHB, TSHR*, TSHZ1, TSLP, TSPAN12, TSPAN17, TSPAN7, TSPO, TSPYL1, TSSC4, TSSK2, TSSK3, TSSK4, TST, TTBK2, TTC19*, TTC21B, TTC37, TTC8, TTI2, TTLL11, TTN, TTPA, TTR, TUBA1A, TUBA8*, TUBB1, TUBB2B, TUBB3*, TUBGCP4, TUBGCP5, TUBGCP6, TUFM, TULP1, TULP3, TUSC3, TWIST2, TXN2, TXNRD2, TYK2, TYMP, TYMS, TYR, TYROBP, TYRP1, UBA1, UBA3, UBAC2, UBD, UBE2A, UBE2B, UBE2I, UBE2NL, UBE3A, UBE3C, UBN2*, UBQLN2, UBR1, UBR3, UBR7, UCHL1, UCP1, UCP2, UCP3, UFD1L, UGT1A1, UGT1A10*, UGT1A3*, UGT1A4*, UGT1A6, UGT1A7*, UGT1A8, UGT1A9*, UGT2A1*, UGT2A3, UGT2B10, UGT2B15, UGT2B28*, UGT2B7, UHRF1BP1, UIMC1, UMOD, UMPS, UNC119*, UNC13D, UNC5C, UNC5CL, UNC80, UNC93A, UNC93B1, UNG, UNKL, UPB1,UPF3B*, UPK3A, UQCRB, UQCRQ, UROC1, UROD, UROS, USB1, USF1, USH1C, USH1G, USH2A, USP15, USP24, USP26, USP46, USP7, USP9X, UTRN, UTS2, UVSSA, VAMP7, VANGL1, VANGL2, VAPB, VAX1*, VCAM1, VCAN, VCL, VCP, VCX3A, VDR, VEGFA*, VHL, VIM, VIMP, VIP, VIPAS39, VIPR2, VKORC1, VLDLR, VMA21*, VNN1*, VPREB1, VPS13A, VPS13B, VPS33B, VPS35, VRK1, VSIG4, VSX1*, VSX2*, VTN, VWF, WAS, WASF3, WDFY3, WDFY4, WDPCP*, WDR11, WDR13, WDR19, WDR35, WDR36, WDR4, WDR45, WDR45B, WDR62, WDR65, WDR72, WDR81, WFS1, WHSC1, WISP3, WNK1, WNK4, WNT10A, WNT10B, WNT3, WNT4*, WNT5A, WNT5B, WNT7A, WRAP53, WRN, WWC1, WWOX, XBP1, XDH, XIAP, XK, XKR4*, XPA*, XPC, XPNPEP2, XPNPEP3, XRCC1, XRCC2, XRCC3, XRCC4, XRCC5, XRCC6, XYLT1*, XYLT2, YAP1, YARS, YARS2, YBX2*, YTHDF2, YWHAE, YY1, ZAN, ZAP70, ZBTB24, ZBTB40, ZBTB41, ZC3H14, ZC3H3, ZC3HAV1, ZCCHC12, ZCCHC13, ZCCHC8, ZDHHC15, ZDHHC8, ZDHHC9, ZEB1, ZEB2, ZFAT, ZFHX3, ZFHX4, ZFP36, ZFP36L1*, ZFP57*, ZFP90, ZFPM2, ZFYVE26, ZFYVE27, ZHX3, ZIC1, ZIC3, ZMPSTE24, ZMYND11, ZNF202, ZNF213, ZNF365*, ZNF41, ZNF469, ZNF507, ZNF513, ZNF526, ZNF592, ZNF627, ZNF644, ZNF674, ZNF711, ZNF75D*, ZNF804A, ZNF81*, ZNHIT6, ZPBP

*Genes having 85-95% coverage in 5% samples.

Note: The average coverage in NGS runs varies from sample to sample


 » Supplementary File 2: Next generation sequencing variant view snapshot of the variants identified in the patients using StrandOmics v5.0 software Top


P7: The patient P7 was found homozygous for the variant c. 2286 + 5G > A (5' splice site) identified in intron 23 of PGAP1 gene. The mutant nucleotide is indicated by an arrow.

P8: The patient P8 was found heterozygous for the variant c. 22C > T (p.Arg8Ter) identified in exon 2 of PAFAH1B1 gene. The wild type and mutant nucleotides are indicated by an arrow.

P9: The patient P9 was found heterozygous for the 3' splice site proximal variation c. 118-14_118-10delTTTAT in intron 3 of the PAFAH1B1 gene. The site of nucleotides deletion is indicated by an arrow.

P16: The patient P16 was detected with a hemizygous variant c. 253_254insC (p.Arg85Profs*110) in exon 1 of the ABCD1 gene. The site of nucleotide insertion is indicated by an arrow.

P19: The patient P19 was found homozygous for the variant c. 116G > A (p.Arg39His) in exon 2 of the SLC17A5 gene. The mutant nucleotide is indicated by an arrow.

Patient P1



Patient P2



Patient P3



Patient P4



Patient P6



Patient P7



Patient P8



Patient P10 (Variant 1)



Patient P10 (Variant 2)



Patient P11



Patient P12 (Variant 1)



Patient P12 (Variant 2)



Patient P13



Patient P14



Patient P15



Patient P17



Patient P18




 » Supplementary File 3: Sanger sequencing electropherogram images of the variants identified in the patients Top


The PCR product of the observed variant was sequenced using Applied BiosystemsTM SeqStudioTM Genetic Analyzer with SeqStudioTM Data Collection Software.





 
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    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2]



 

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