Neri Sabrina, Maia Nuno, Fortuna Ana M, Damasio Joana, Coale Elizabeth, Willis Mary, Jorge Paula, Højte Anne F, Fenger Christina D, Møller Rikke S, Bayat Allan
Danish Epilepsy Centre, Department of Epilepsy Genetics and Personalized Medicine, DK-4293, Dianalund, Denmark; Department of Medical and Surgical Sciences, "Magna Graecia" University, Catanzaro, Italy.
Unidade de Genética Molecular, Centro de Genética Médica Jacinto de Magalhães (CGM), Centro Hospitalar Universitário do Porto (CHUPorto), Porto, Portugal; UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal, and ITR - Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal.
Eur J Med Genet. 2022 Nov;65(11):104624. doi: 10.1016/j.ejmg.2022.104624. Epub 2022 Sep 18.
Ritscher-Schinzel syndrome (RTSCS) is a rare genetic condition characterized by peculiar craniofacial features and cerebellar and cardiovascular malformations. To date, four genes are implicated in this condition. The first two genes described were the autosomal recessive inherited gene WASHC5 associated with Ritscher-Schinzel syndrome 1 (RTSCS1), and CCDC22, an X-linked recessive gene causing Ritscher-Schinzel syndrome 2 (RTSCS2). In recent years, two other genes have been identified: VPS35L (RTSCS3) and DPYSL5 (RTSCS4). Only few patients with a molecular diagnosis of RTSCS have been reported, leaving the phenotypical spectrum and genotype-phenotype correlations ill-defined. We expand the number of genetically confirmed patients with RTSCS1 and 2; reporting three live born and three terminated pregnancies from two unrelated families. Four siblings carried compound heterozygous variants in WASHC5 while two siblings harboured a hemizygous CCDC22 variant. The most common findings in all patients were craniofacial dysmorphism, particularly macrocephaly, down slanted palpebral fissures and low set-ears. Developmental delay, intellectual disability and ataxic gait were present in all patients. One of the patients with the CCDC22 variant presented pubertas tarda. Elevation of nuchal translucency was observed in the first trimester ultrasound in three foetuses with compound heterozygous variants in WASHC5. None of the patients had epilepsy. The pre- and postnatal findings of this cohort expand the known phenotype of RTSCS1 and 2, with direct impact on postnatal outcome, management, and familial counseling.
里切尔-申策尔综合征（RTSCS）是一种罕见的遗传性疾病，其特征为特殊的颅面特征以及小脑和心血管畸形。迄今为止，有四个基因与该疾病相关。最早描述的两个基因是与里切尔-申策尔综合征1（RTSCS1）相关的常染色体隐性遗传基因WASHC5，以及导致里切尔-申策尔综合征2（RTSCS2）的X连锁隐性基因CCDC22。近年来，又鉴定出了另外两个基因：VPS35L（RTSCS3）和DPYSL5（RTSCS4）。仅有少数经分子诊断为RTSCS的患者被报道，使得表型谱以及基因型-表型相关性尚不明确。我们增加了经基因确诊的RTSCS1和RTSCS2患者数量；报告了来自两个无关家庭的三例活产儿和三例终止妊娠病例。四个兄弟姐妹携带WASHC5的复合杂合变异，而两个兄弟姐妹携带CCDC22的半合子变异。所有患者中最常见的表现是颅面畸形，尤其是巨头畸形、睑裂向下倾斜和低位耳。所有患者均存在发育迟缓、智力障碍和共济失调步态。一名携带CCDC22变异的患者出现青春期延迟。在孕早期超声检查中，发现三名携带WASHC5复合杂合变异的胎儿颈部透明带增厚。所有患者均无癫痫发作。该队列的产前和产后检查结果扩展了已知的RTSCS1和RTSCS2表型，对产后结局、管理和家族咨询有直接影响。
