Clin Genet 2014: 86: 598–600 Printed in Singapore. All rights reserved
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12338
Letter to the Editor
Using a combination of whole-exome sequencing and homozygosity mapping to identify a novel mutation of SCARB2 To the Editor: Progressive myoclonus epilepsy (PME) is a heterogeneous disorder associated with diverse clinical features and causative genes. When the clinical manifestations do not fit the canonical model, it becomes exceedingly difficult to screen all the known genetic mutations that can cause PME, let alone those that have yet to be revealed. We focused on two patients of related parents with action myoclonus and seizures. Patient 1 (the proband, II:5) was the third child of parents who were related in the third degree of consanguinity (Fig. 1c). She developed tremor in her two hands when writing or fetching things at the age of 21. A gait disorder developed at the age of 22. Since then, she fell easily, especially when scared. The same year, she developed dysarthria and drinking cough. At age 25, she could not walk without aid. In February 2009, when the patient was 25 years old, she suffered a generalized tonic–clonic seizure. Generalized seizures were recurrent since that time, averaging 2–3 times per month. The symptoms could not be controlled even when taking sodium valproate 400 mg t.i.d. However, her intelligence was intact. The patient underwent several examinations. The results of brain MRI scan, electromyography, cerebrospinal fluid examination and renal function were normal. Twenty-four-hour video electroencephalography (EEG) revealed no paradoxical discharge. Brainstem auditory-evoked responses indicated minor bilateral impairment, and the somatosensory-evoked potential and motor-evoked potential were normal. Patient 2 (II:4) was the elder sister of Patient 1. She was in good health until the age of 27, when she developed tremor in her hands. Her action myoclonus, gait problems and dysarthria appeared successively and have progressed in recent years. Now, at age 34, she was able to walk a short distance with aid, and her intelligence was preserved. Unlike her sister, she did not suffer from seizures. The results of her examinations were comparable with her sister’s. To locate the causative mutation, whole-exome sequencing was performed using genomic DNA from Patients 1 and 2. Given that their parents were related, we focused on homozygosity for the same recessive
598
mutant allele and narrowed our range to 23 SNPs and 35 indels. Because disease-linked variants are reported to be concentrated in homozygous regions longer than 5 Mb, the data from whole-exome sequencing were examined for large stretches of homozygous regions of length 5 or more Mb (1). Only two homozygous regions that fulfilled our selection criteria were identified. After comparing the SNPs and indels with the homozygosity regions, we finally identified the homozygous nonsense mutation (c.1270 C>T, p. R424X) in exon 11 of SCARB2 gene which was co-segregating within the family. The siblings’ parents and their older brother were all carriers of the heterozygous mutation with normal phenotypes, as were the children of Patient 1 and her brother (III:1, III:2, III:3). The novel mutation was undetected in nine other PME patients and 500 normal controls using Sanger sequencing (Fig. 1a). To explain the clinical heterogeneity of the affected siblings despite the identical mutation, we examined data from whole-exome sequencing for possible mutations in epilepsy-related genes. A heterozygous mutation (c.1286G>A, p.C429Y) was detected in another epilepsy-related gene, KCNQ2 , in the affected sibling with frequent seizures but was not detected in her older sister without seizures (Fig. 1b). This mutation was inherited from their father (I:1) and absent in 500 normal controls. This is the first report of PME caused by a SCARB2 mutation in China. To date,
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12338
Letter to the Editor
Using a combination of whole-exome sequencing and homozygosity mapping to identify a novel mutation of SCARB2 To the Editor: Progressive myoclonus epilepsy (PME) is a heterogeneous disorder associated with diverse clinical features and causative genes. When the clinical manifestations do not fit the canonical model, it becomes exceedingly difficult to screen all the known genetic mutations that can cause PME, let alone those that have yet to be revealed. We focused on two patients of related parents with action myoclonus and seizures. Patient 1 (the proband, II:5) was the third child of parents who were related in the third degree of consanguinity (Fig. 1c). She developed tremor in her two hands when writing or fetching things at the age of 21. A gait disorder developed at the age of 22. Since then, she fell easily, especially when scared. The same year, she developed dysarthria and drinking cough. At age 25, she could not walk without aid. In February 2009, when the patient was 25 years old, she suffered a generalized tonic–clonic seizure. Generalized seizures were recurrent since that time, averaging 2–3 times per month. The symptoms could not be controlled even when taking sodium valproate 400 mg t.i.d. However, her intelligence was intact. The patient underwent several examinations. The results of brain MRI scan, electromyography, cerebrospinal fluid examination and renal function were normal. Twenty-four-hour video electroencephalography (EEG) revealed no paradoxical discharge. Brainstem auditory-evoked responses indicated minor bilateral impairment, and the somatosensory-evoked potential and motor-evoked potential were normal. Patient 2 (II:4) was the elder sister of Patient 1. She was in good health until the age of 27, when she developed tremor in her hands. Her action myoclonus, gait problems and dysarthria appeared successively and have progressed in recent years. Now, at age 34, she was able to walk a short distance with aid, and her intelligence was preserved. Unlike her sister, she did not suffer from seizures. The results of her examinations were comparable with her sister’s. To locate the causative mutation, whole-exome sequencing was performed using genomic DNA from Patients 1 and 2. Given that their parents were related, we focused on homozygosity for the same recessive
598
mutant allele and narrowed our range to 23 SNPs and 35 indels. Because disease-linked variants are reported to be concentrated in homozygous regions longer than 5 Mb, the data from whole-exome sequencing were examined for large stretches of homozygous regions of length 5 or more Mb (1). Only two homozygous regions that fulfilled our selection criteria were identified. After comparing the SNPs and indels with the homozygosity regions, we finally identified the homozygous nonsense mutation (c.1270 C>T, p. R424X) in exon 11 of SCARB2 gene which was co-segregating within the family. The siblings’ parents and their older brother were all carriers of the heterozygous mutation with normal phenotypes, as were the children of Patient 1 and her brother (III:1, III:2, III:3). The novel mutation was undetected in nine other PME patients and 500 normal controls using Sanger sequencing (Fig. 1a). To explain the clinical heterogeneity of the affected siblings despite the identical mutation, we examined data from whole-exome sequencing for possible mutations in epilepsy-related genes. A heterozygous mutation (c.1286G>A, p.C429Y) was detected in another epilepsy-related gene, KCNQ2 , in the affected sibling with frequent seizures but was not detected in her older sister without seizures (Fig. 1b). This mutation was inherited from their father (I:1) and absent in 500 normal controls. This is the first report of PME caused by a SCARB2 mutation in China. To date,
