28595573 Visualization

The proband (II-2 in Fig.2) is a 45 Age - year Age old Age woman Sex , who first presented Clinical_event to our university Biological_structure hospital Biological_structure at Date the Date age Date of Date 35 Date and was referred to us because of her pregnancy History .
She has congenital History deafness History , first experienced syncope Sign_symptom at the age Date of Date 3 Date , and was diagnosed with epilepsy History .
She was treated with anti Medication - epilepsy Medication medications Medication ; however, she subsequently experienced several Detailed_description instances Detailed_description of syncope Sign_symptom .
At the age Date of Date 13 Date , she had a syncope Sign_symptom event, and was suspected of having JLNS Disease_disorder because of her congenital deafness and prolonged Sign_symptom QT Sign_symptom interval Sign_symptom .
Her syncope Sign_symptom was diagnosed as an arrhythmic Sign_symptom episode Sign_symptom when she was aware of tachycardia Sign_symptom and as epilepsy Disease_disorder when she was not.
She also had a subarachnoid Sign_symptom hemorrhage Sign_symptom at the age Date of Date 29 Date .
When she first presented Clinical_event at our hospital Nonbiological_location , she was not taking beta Medication - blockers Medication , because of a history of asthma History , but was taking mexiletine Medication in addition to phenytoin Medication .
Her QTc Diagnostic_procedure was found to be prolonged Lab_value ( 584 Lab_value ms Lab_value ) at presentation Clinical_event and administration of atenolol Medication was initiated.
She delivered Clinical_event her baby Subject (III-1 in Fig.2) through Caesarean Therapeutic_procedure operation Therapeutic_procedure at our hospital Nonbiological_location at the age Date of Date 35 Date .
At Date 37 Date , she delivered Clinical_event her second Subject baby Subject (III-2 in Fig.2) through Caesarean Therapeutic_procedure operation Therapeutic_procedure at our hospital Nonbiological_location .
Despite administration of beta Medication - blockers Medication , her QTc Diagnostic_procedure remained prolonged Lab_value ( 600 Lab_value msec Lab_value at the age Date of Date 37 Date , 780 Lab_value msec Lab_value at 44 Date ) (Figs.2 and ​3a), which is not unexpected because treatment with beta-blockers in LQTS1 is not expected to overtly reduce QTc [18].
However, she continued to experience occasional Detailed_description syncope Sign_symptom and finally underwent an implantable Therapeutic_procedure cardioverter Therapeutic_procedure defibrillator Therapeutic_procedure ( ICD Therapeutic_procedure ) operation at 38 Date years Date of Date age Date .
Subsequently, she is in a stable Sign_symptom clinical Sign_symptom condition Sign_symptom .
Because the proband was suspected of JLNS Disease_disorder and both Subject infants Subject had a measured Family_history QTc Family_history of Family_history 500 Family_history ms Family_history or Family_history greater Family_history within Family_history 1 Family_history month Family_history after Family_history birth Family_history , beta Family_history blockers Family_history were initiated and both children remain in stable Family_history condition Family_history at Family_history ages Family_history 10 Family_history and Family_history 8 Family_history (Figs.2 and 3b, c).
QTc Family_history of the son Subject (III-1 in Fig.2) was measured as 500 Family_history ms Family_history one Family_history month Family_history after Family_history birth Family_history , while the QTc Family_history of his sister Subject (III-2) was 530 Family_history ms Family_history at Family_history birth Family_history .
The History father History (I-1) and History mother History (I-2) of History the History proband History were History first History cousins History .
There is no Family_history history Family_history of Family_history sudden Family_history unexplained Family_history syncope Family_history or Family_history death Family_history of Family_history children Family_history or Family_history adults Family_history in the immediate Subject family Subject members Subject , despite the prolonged QTc of the children.
Clinical Diagnostic_procedure evaluation Diagnostic_procedure and consultation Clinical_event of the proband and her family members were performed at Chiba Nonbiological_location University Nonbiological_location Hospital Nonbiological_location .
Clinical phenotypes were deduced from the clinical history, physical Diagnostic_procedure examinations Diagnostic_procedure , and ECG Diagnostic_procedure .
Blood Diagnostic_procedure samples Diagnostic_procedure were collected from the proband and her family members following genetic Clinical_event counseling Clinical_event , and written informed consent was obtained prior to sample collection.
Genomic Diagnostic_procedure DNA Diagnostic_procedure was isolated from peripheral Biological_structure blood Biological_structure lymphocytes Biological_structure according to established protocols at our laboratory [19].
Entire coding exons, including the intronic boundaries of the genes, of KCNQ1 Detailed_description (NCBI ref: NM_000218) and other LQT Detailed_description causative Detailed_description genes Detailed_description ( KCNH2, Detailed_description SCN5A, Detailed_description KCNE1, Detailed_description KCNE2, Detailed_description KCNJ2, Detailed_description SCN4B, Detailed_description KCNJ5 Detailed_description ) were amplified by polymerase Diagnostic_procedure chain Diagnostic_procedure reaction Diagnostic_procedure ( PCR Diagnostic_procedure ), according to established protocols in our laboratory.
Briefly, 30–100 ng Detailed_description of Detailed_description genomic Detailed_description DNA Detailed_description was subjected to PCR Coreference amplification Coreference with DNA Detailed_description polymerase Detailed_description ( PrimeSTAR Detailed_description GXL Detailed_description DNA Detailed_description Polymerase; Detailed_description Takara Detailed_description Bio Detailed_description Inc., Detailed_description Kusatsu, Detailed_description Japan Detailed_description ) and primer Detailed_description sets Detailed_description .
The amplicons Detailed_description were subjected to conventional Detailed_description sequencing Diagnostic_procedure with Sanger Detailed_description sequencers Detailed_description ( Applied Detailed_description Biosystems Detailed_description 3730/3130 Detailed_description DNA Detailed_description analyzers; Detailed_description Thermo Detailed_description Fisher Detailed_description Scientific, Detailed_description Waltham, Detailed_description MA, Detailed_description USA Detailed_description ).
The sequence data were processed Detailed_description with Detailed_description Gene Detailed_description Codes Detailed_description Sequencher Detailed_description Software Detailed_description ( Takara Detailed_description Bio Detailed_description Inc. Detailed_description ) and mapped Detailed_description to Detailed_description the Detailed_description human Detailed_description genome Detailed_description sequence Detailed_description ( build Detailed_description GRCh37/hg19 Detailed_description ).
Genetic Diagnostic_procedure analysis Diagnostic_procedure was performed to screen all coding exons and the exon–intron boundaries of the KCNQ1 Detailed_description gene Detailed_description (NCBI ref: NM_000218.2, NP_000209.2) with concurrent screening of other LQT Detailed_description causative Detailed_description genes Detailed_description ( KCNH2, Detailed_description SCN5A, Detailed_description KCNE1, Detailed_description KCNE2, Detailed_description KCNJ2, Detailed_description SCN4B, Detailed_description KCNJ5 Detailed_description ).
We detected a novel homozygous Sign_symptom nonsense Sign_symptom variant Sign_symptom , NM_000218.2:c.115G Detailed_description   > Detailed_description   T Detailed_description (p.Glu39X, in exon 1a), in the KCNQ1 gene of the proband, as well as a homozygous Sign_symptom common Sign_symptom variant Sign_symptom ( NM_000218.2:c.1343C Detailed_description   > Detailed_description   G Detailed_description , p.Pro448Arg) (Additional file 1: Table S1).
Genetic Diagnostic_procedure screening Diagnostic_procedure of her mother Subject (I-2) and children Subject (III-1 and III-2) revealed that they were heterozygous Family_history for Family_history the Family_history nonsense Family_history variant Family_history (Fig.2).
Her husband Subject (II-3) was also screened and found to be heterozygous Family_history for Family_history the Family_history common Family_history variant Family_history (NM_000218.2:c.1343C > G, p.Pro448Arg).
The History proband History is History a History child History from History a History first History - cousin History marriage History , and we have concluded the homozygous Sign_symptom nonsense Sign_symptom variant Sign_symptom in the proband is the cause of her JLNS1 Disease_disorder .
The proband was negative for pathogenic Sign_symptom variants Sign_symptom in Sign_symptom other Sign_symptom LQT Sign_symptom causative Sign_symptom genes Sign_symptom , including the KCNE1 gene (Additional file 1: Table S1).