Early-onset nucleotide excision repair disorders with neurological impairment: Clues for early diagnosis and prognostic counseling.,Clinical Genetics

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Early-onset nucleotide excision repair disorders with neurological impairment: Clues for early diagnosis and prognostic counseling.
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-06-17 , DOI: 10.1111/cge.13798
Sarah Baer _{1,

2} , Cathy Obringer ₃ , Sophie Julia ₄ , Jameleddine Chelly ₂ , Yline Capri ₅ , Domitille Gras ₆ , Geneviève Baujat ₇ , Têmis Maria Felix ₈ , Berenice Doray ₉ , Jaime Sanchez Del Pozo ₁₀ , Lina M Ramos ₁₁ , Lydie Burglen ₁₂ , Vincent Laugel _{1,

3} , Nadège Calmels _{2,

3}

Affiliation

Service de Pédiatrie 1, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Laboratoires de Diagnostic Génétique, Institut de génétique médicale d'Alsace, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Laboratoire de Génétique médicale, Institut de génétique médicale d'Alsace, Faculté de Médecine de Strasbourg, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Service de Génétique Médicale, CHU de Toulouse - Hôpital Purpan, Toulouse, France.
Service de Génétique Médicale, AP-HP Robert-Debré, Paris, France.
Service de Neurologie Pédiatrique, AP-HP Robert-Debré, Paris, France.
Centre de Référence Maladies Osseuses Constitutionnelles, Département de Génétique, Hôpital Necker-Enfants Malades, Institut Imagine, Paris, France.
Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil.
Service de Génétique Médicale, Centre Hospitalier Universitaire Félix Guyon, Bellepierre, France.
Pediatric Endocrinology and Dysmorphology Unit, Hospital Universitario, Madrid, Spain.
Pediatric Hospital of Coimbra, Coimbra, Portugal.
Centre de référence des malformations et maladies congénitales du cervelet, Département de génétique et embryologie médicale, APHP, GHUEP, Hôpital Trousseau, Paris, France.

Nucleotide excision repair associated diseases comprise overlapping phenotypes and a wide range of outcomes. The early stages still remain under‐investigated and underdiagnosed, even although an early recognition of the first symptoms is of utmost importance for appropriate care and genetic counseling. We systematically collected clinical and molecular data from the literature and from newly diagnosed NER patients with neurological impairment, presenting clinical symptoms before the age of 12 months, including foetal cases. One hundred and eighty‐five patients were included, 13 with specific symptoms during foetal life. Arthrogryposis, microcephaly, cataracts, and skin anomalies are the most frequently reported signs in early subtypes. Non ERCC6/CSB or ERCC8/CSA genes are overrepresented compared to later onset cohorts: 19% patients of this cohort presented variants in ERCC1, ERCC2/XPD, ERCC3/XPB or ERCC5/XPG. ERCC5/XPG is even the most frequently involved gene in foetal cases (10/13 cases, [4/7 families]). In this cohort, the mutated gene, the age of onset, the type of disease, severe global developmental delay, IUGR and skin anomalies were associated with earlier death. This large survey focuses on specific symptoms that should attract the attention of clinicians towards early‐onset NER diagnosis in foetal and neonatal period, without waiting for the completeness of classical criteria.

中文翻译：

具有神经功能障碍的早期发病的核苷酸切除修复疾病：早期诊断和预后咨询的线索。

核苷酸切除修复相关疾病包括重叠的表型和广泛的结果。尽管尽早识别出最初的症状对于适当的护理和遗传咨询极为重要，但早期阶段仍未得到充分的研究和诊断。我们从文献和新诊断出的神经系统受损的NER患者中系统地收集了临床和分子数据，在包括胎儿在内的12个月大之前就出现了临床症状。包括185例患者，其中13例在胎儿生命中有特定症状。关节亚型，小头畸形，白内障和皮肤异常是早期亚型中最常报告的体征。非ERCC6 / CSB或ERCC8 / CSA与后来的发病队列相比，这些基因的代表性较高：该队列中有19％的患者呈现ERCC1，ERCC2 / XPD，ERCC3 / XPB或ERCC5 / XPG变异。ERCC5 / XPG甚至是胎儿病例（10/13例，[4/7家族]）中涉及最频繁的基因。在该队列中，突变的基因，发病年龄，疾病类型，严重的整体发育延迟，IUGR和皮肤异常与较早死亡相关。这项大型调查关注的特定症状应引起临床医生的注意，以期在胎儿和新生儿期进行NER早期诊断，而无需等待经典标准的完成。

更新日期：2020-06-17

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