Genetic analysis of a child with D bifunctional protein deficiency born to a consanguineous pedigree
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目的 分析1例由近亲婚配所致D双功能蛋白缺乏症(DBPD)患儿的遗传学病因。 方法 选取2022年1月6日因"肌张力低、全面发育落后"就诊于海南医学院第一附属医院的1例DBPD患儿作为研究对象，并收集其临床资料及其家系调查资料。提取患儿及父母、姐姐的外周血样，提取基因组DNA，应用全外显子组测序对患儿进行基因变异检测，对候选变异进行Sanger测序家系验证。应用生物信息软件预测变异位点的致病性，诊断患儿所患疾病。 结果 患儿为2岁9个月女性，临床表现为肌张力低下、发育迟缓、抬头不稳，感音神经性耳聋。血清长链脂肪酸增高，听性脑干诱发电位双侧耳90 dBnHL刺激均未能引出V波，头颅MRI提示胼胝体变薄，白质发育不良，患儿父母系近亲婚配，其长女表型正常，无D双功能蛋白缺乏症相关临床症状，其儿子出生当天频繁惊厥、肌张力低及喂养困难，生后1个半月夭折。基因测序结果显示患儿HSD17B4基因存在c.483G>T(p.Gln161His)纯合变异，父母、姐姐均携带HSD17B4基因c.483G>T(p.Gln161His)者。根据美国医学遗传学与基因组学学会变异评级相关指南，c.483G>T(p.Gln161His)变异评级为致病性变异(PM1+PM2_Supporting+PP1+PP3+PP4)。 结论 父母近亲婚配导致患儿HSD17B4基因携带c.483G>T(p.Gln161His)纯合变异，考虑为是患儿的遗传学病因。 Objective To explore the genetic etiology of a child with D bifunctional protein deficiency (DBPD) born to a consanguineous pedigree. Methods A child with DBPD who was admitted to the First Affiliated Hospital of Hainan Medical College on January 6, 2022 due to hypotonia and global developmental delay was selected as the study subject. Clinical data of her pedigree members were collected. Peripheral blood samples of the child, her parents and elder sisters were collected and subjected to whole exome sequencing. Candidate variant was validated by Sanger sequencing and bioinformatic analysis. Results The child, a 2-year-and-9-month-old female, had featured hypotonia, growth retardation, unstable head lift, and sensorineural deafness. Serum long-chain fatty acids were elevated, and auditory brainstem evoked potentials had failed to elicit V waves in both ears with 90 dBnHL stimulation. Brain MRI revealed thinning of corpus callosum and white matter hypoplasia. The child's parents were secondary cousins. Their elder daughter had a normal phenotype and no clinical symptoms related to DBPD. Elder son had frequent convulsions, hypotonia and feeding difficulties after birth, and had died one and a half month later. Genetic testing revealed that the child had harbored homozygous c. 483G>T(p.Gln161His) variants of theHSD17B4 gene, for which both of her parents and elder sisters were carriers. Based on the guidelines from the American College of Medical Genetics and Genomics, the c. 483G>T(p.Gln161His) was rated as a pathogenic variant (PM1+ PM2_Supporting+ PP1+ PP3+ PP4). Conclusion The homozygous c. 483G>T (p.Gln161His) variants of theHSD17B4 gene caused by the consanguineous marriage probably underlay the DBPD in this child.
Objective To explore the genetic etiology of a child with D bifunctional protein deficiency (DBPD) born to a consanguineous pedigree. Methods A child with DBPD who was admitted to the First Affiliated Hospital of Hainan Medical College on January 6, 2022 due to hypotonia and global developmental delay was selected as the study subject. Clinical data of her pedigree members were collected. Peripheral blood samples of the child, her parents and elder sisters were collected and subjected to whole exome sequencing. Candidate variant was validated by Sanger sequencing and bioinformatic analysis. Results The child, a 2-year-and-9-month-old female, had featured hypotonia, growth retardation, unstable head lift, and sensorineural deafness. Serum long-chain fatty acids were elevated, and auditory brainstem evoked potentials had failed to elicit V waves in both ears with 90 dBnHL stimulation. Brain MRI revealed thinning of corpus callosum and white matter hypoplasia. The child's parents were secondary cousins. Their elder daughter had a normal phenotype and no clinical symptoms related to DBPD. Elder son had frequent convulsions, hypotonia and feeding difficulties after birth, and had died one and a half month later. Genetic testing revealed that the child had harbored homozygous c. 483G>T(p.Gln161His) variants of theHSD17B4 gene, for which both of her parents and elder sisters were carriers. Based on the guidelines from the American College of Medical Genetics and Genomics, the c. 483G>T(p.Gln161His) was rated as a pathogenic variant (PM1+ PM2_Supporting+ PP1+ PP3+ PP4). Conclusion The homozygous c. 483G>T (p.Gln161His) variants of theHSD17B4 gene caused by the consanguineous marriage probably underlay the DBPD in this child.
ConsanguinityD-bifunctional protein deficiencyHypotoniaDevelopmental delayHSD17B4 geneChild
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