xyz collected - dr lal pathlabs · a/c status: p ref by : dr. xxxxx report status : final page2of3...

LPL - LPL-ROHINI (NATIONAL REFERENCE LAB)

SECTOR - 18, BLOCK -E ROHINI

DELHI 110085

Name : XYZ Collected : 4/4/2018 8:39:00AMReceived : 4/4/2018 8:42:06AM

Lab No. : xxxxxxxxx Age: 00 Years Gender: Male Reported : 4/4/2018 2:46:10PM

A/c Status: P Ref By : Dr. xxxxx Report Status : Final

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TEST DETAILS:

Test Name MethodNx Gen Clinical Exome Test Next Generation Sequencing (NGS)

RESULTS

Likely Pathogenic variant detected. One copy of c.3395G>A (p.W1132*) likely pathogenic variant in KCNT1 genewas detected in this individual.

For other findings kindly see the table "Diagnostic findings not related to the phenotype.

INTERPRETATION:

A blood sample collected from this individual was referred to our laboratory for molecular testing using Next Generation Sequencing (NGS)based gene panel. As per the clinical information provided to the lab, this individual presented with psychomotor agitation, seizures, frequentdystonia and severe cognitive impairment.

Diagnostic Findings related to phenotype:

Based on the clinical information provided to the laboratory, the following variants related to or possibly related to this individual's phenotypewere detected:

Gene MIM# Disease(Inheritance) Exon Nucleotide

ChangeAmino acid

Change Zygosity Type

KCNT1 608167

Epilepsy, nocturnalfrontal lobe 5 (AD),

Epilepticencephalopathy,early infantile 14

(AD)

Ex-29 c.3395G>A p.W1132* Homozygoys Likelypathogenica

Abbreviations used in this table: AD - Autosomal Dominant

* KCNT1 Transcript Number: NM_ 020822.2

a. The detected exonic variant c.3395G>A (p.W1132*) in KCNT1 gene is a null variant in a gene where loss of function (LOF) is a knownmechanism of disease. Mutations on the gene KCNT1 has been associated with epileptic disorders1. This variant was neither reported inliterature nor by our laboratory earlier. It was found at a very low frequency in the general population6-9 and multiple lines of computationalevidence support a deleterious effect on the gene or gene product3-4. According to the ACMG guidelines for variant interpretation, this variantis being classified as likely pathogenic2.

Diagnostic Findings not related to phenotype:

No significant variant was detected in this individual

Comments:The above mentioned result must be interpreted in context to the thorough medical history of the individual.



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Recommendations:Targeted genetic testing of the detected heterozygous variant for all the first degree relatives is being recommended. Genetic counselling isrecommended.

We offer targeted analysis for family members at risk for carrying the pathogenic variant identified in this individual.

Variants:A list of variants identified in this individual is available upon request. Visit ACMG guideline2 for current classification of variants. Theseclassifications may change over time as more information about the sequencing data and this individual's clinical phenotype becomesavailable.

Note:This analysis cannot detect single and multi-exon deletions and duplications. Pathogenic variants may also be present within regions whichwere not analyzed (e.g. introns, promoter and enhancer regions, and long repeats).Variants are evaluated by their reported frequency6-9.

Variants that have a population frequency greater than expected given the prevalence of the disease in the general population are consideredto be benign variants. Silent variants are not reported unless known to be pathogenic or other evidence suggests potential disruption ofsplicing.

The interpretations may change overtime as more information about the exome and this individual’s clinical phenotype becomes available.Visit ACMG guideline2 for current classification of variants. Only variants in gene associated with the phenotype observed in this individual,or thought to be clinically relevant for the proband are reported here. These include pathogenic or likely pathogenic variants in genes describedin the ACMG Recommendation for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing as requested by the patient5.These results must be interpreted in the context of this individual's clinical and biochemical profile.

METHODOLOGY:

NGS-Laboratory:In solution hybridization of the coding exons and flanking intronic regions within the genes tested was performed on this individual's genomicDNA. Direct sequencing of the amplified captured regions was performed using next generation short base pair read sequencing using NGSplatform. Low coverage regions, if any, are limited to ̴2% orless of the exons/nucleotides included in this panel. A list of these regions isavailable upon request. Sanger sequencing confirmation of the reported variants has not been performed.

Computational Analysis:

Alignment to the human reference genome (Hg19) and variant calling is performed using GATK. Bioinformatics pipeline, in conjunction withexternal data sources, annotates variants identified in the targeted regions. For each transcript listed, the analyzed region includes the codingexons and ± 10bp of flanking intronic region on both sides of each exon.

Certain deep intronic sites are also targeted. In some cases, due to the complexity of the sequence, not all variants in the flanking intronicsequence are able to be analyzed.

Data analysis:

Only variants (SNVs/smallindels)in the coding region and the flanking intronic regions (±10bp)with a minor allele frequency (MAF)<5% areevaluated All reported variants meet internal quality control standards. Minor allele frequencies are taken from the following databases: 1000Genomes, dbSNP, NHLBI Exome Sequencing Project (ESP), Exome Aggregation Consortium, and an in-house database.

REFERENCES:

1. Barcia G et al. (2012); Nat Genet. 44 (11): 1255-92. Richards S et al. (2015); Genet Med.17(5):405-243. Kumar P et al. (2009); NatProtoc, 4(7):1073-814. Adzhubei IA et al. (201O); NatMethods,7(4):248-95. Kalia SS et al.(2017);Genet Med. 19(2):249-255



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6. 1000Genomes: browser. 1000genomes.org/7. NCBI db SNP:www.ncbi.nih.gov/dbSNP8. Exome Variant Server:evs.gs.washington.edu/EVS/EVS9. Exome Aggregation Consortium(ExAC):exac.broadinstitute.org/

---- End of report ----

Dr. Anand C AnnanMD (Path), PhD (Molecular & Cellular

Pathology), Head Oncopathology

Dr. Atul ThataiPhD, National Head

R&D Molecular Diagnostics

Dr. Gaurav VermaPhD (Clinical Genetics)

Sr. Manager – Scientific Affairs

xyz collected - dr lal pathlabs · a/c status: p ref by : dr. xxxxx report status : final page2of3...

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