甲状腺过氧化物酶(TPO)的纯合突变在两个家族的智力残疾、发育迟缓、听力和视力异常的甲状腺功能减退症中:未经治疗的TPO缺乏症的严重表现带来诊断难题。

IF 2.5 3区 工程技术 Q2 BIOLOGY Yale Journal of Biology and Medicine Pub Date : 2023-09-29 eCollection Date: 2023-09-01 DOI:10.59249/SSRG6507
Syeda Farwa Naqvi, Esra Yıldız-Bölükbaşı, Muhammad Afzal, Gökhan Nalbant, Sara Mumtaz, Aslıhan Tolun, Sajid Malik
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引用次数: 0

摘要

智力残疾包括智力、学习和认知技能受损,以及心理运动技能下降的行为能力。ID的可预防原因之一是先天性甲状腺功能减退症(CH),这可能是由于甲状腺过氧化物酶(TPO)的双等位基因突变。在没有新生儿筛查项目的中低收入国家,CH存在很大的ID和长期发病风险。我们报告了两个巴基斯坦大家庭,共有16名CH患者。进行了详细的临床和行为评估、基于SNP的纯合子定位、连锁分析和外显子组测序。最初,受影响的个体被称为患有ID(16名患者中有11名)和发育迟缓(14名)。次要/相关特征为言语失用症(13例)、甲状腺肿(12例)、身材矮小(11例)、肢体张力减退(14例)、未青春期发作(10例中有5例年龄≥14岁)、高度近视(8例)、肌肉痉挛(6例),在某些情况下,可变小头症和遗尿/尿崩、痉挛、慢性疲劳和其他行为症状,这些都不是CH的特征。分子遗传学分析导致在TPO中发现纯合变体:家族1中的新错义变体c.719A>G(p.Asp240Gly)和家族2中的罕见变体c.2315A>G(p.Tyr772Cys)。在低资源国家,新生儿筛查项目不包括CH检测,由于未经治疗的CH,神经发育障碍的负担可能会增加。其次,在父母高血亲导致隐性疾病高患病率的背景下,TPO缺乏症的严重表现模拟了造成诊断困境的广泛的神经和其他表现。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Homozygous Mutations in Thyroid Peroxidase (TPO) in Hypothyroidism with Intellectual Disability, Developmental Delay, and Hearing and Ocular Anomalies in Two Families: Severe Manifestation of Untreated TPO-deficiency Poses a Diagnostic Dilemma.

Intellectual disability (ID) involves compromised intellectual, learning and cognitive skills, and behavioral capabilities with reduced psychomotor skills. One of the preventable causes of ID is congenital hypothyroidism (CH), which may be due to biallelic mutations in thyroid peroxidase (TPO). In low- and middle-income countries with no newborn screening programs, CH poses a great risk of ID and long-term morbidity. We report two large Pakistani families with a total of 16 patients afflicted with CH. Detailed clinical and behavioral assessments, SNP-based homozygosity mapping, linkage analysis, and exome sequencing were performed. Initially, affected individuals were referred as suffering ID (in 11 of 16 patients) and developmental delay (in 14). Secondary/associated features were verbal apraxia (in 13), goiter (in 12), short stature (in 11), limb hypotonia (in 14), no pubertal onset (five of 10 of age ≥14 years), high myopia (in eight), muscle cramps (in six), and in some, variable microcephaly and enuresis/encopresis, fits, chronic fatigue, and other behavioral symptoms, which are not characteristics of CH. Molecular genetic analyses led to the discovery of homozygous variants in TPO: novel missense variant c.719A>G (p.Asp240Gly) in family 1 and rare c.2315A>G (p.Tyr772Cys) in family 2. In low-resource countries where neonatal screening programs do not include a CH test, the burden of neurodevelopmental disorders is likely to be increased due to untreated CH. Secondly, in the background of the high prevalence of recessive disorders due to high parental consanguinity, the severe manifestation of TPO-deficiency mimics a wide range of neurological and other presentations posing a diagnostic dilemma.

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Yale Journal of Biology and Medicine
Yale Journal of Biology and Medicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
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期刊介绍: The Yale Journal of Biology and Medicine (YJBM) is a graduate and medical student-run, peer-reviewed, open-access journal dedicated to the publication of original research articles, scientific reviews, articles on medical history, personal perspectives on medicine, policy analyses, case reports, and symposia related to biomedical matters. YJBM is published quarterly and aims to publish articles of interest to both physicians and scientists. YJBM is and has been an internationally distributed journal with a long history of landmark articles. Our contributors feature a notable list of philosophers, statesmen, scientists, and physicians, including Ernst Cassirer, Harvey Cushing, Rene Dubos, Edward Kennedy, Donald Seldin, and Jack Strominger. Our Editorial Board consists of students and faculty members from Yale School of Medicine and Yale University Graduate School of Arts & Sciences. All manuscripts submitted to YJBM are first evaluated on the basis of scientific quality, originality, appropriateness, contribution to the field, and style. Suitable manuscripts are then subject to rigorous, fair, and rapid peer review.
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