Racine Caroline, Garde Aurore, Martz Olivia, Safraou Hana, Eluard Vinciane, Rousseau Thierry, Marle Nathalie, Harizay Fara T, Martin Laurent, Maraval Julien, Bruel Ange-Line, Philippe Christophe, Thauvin-Robinet Christel, Faivre Laurence
Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU Dijon Bourgogne, FHU TRANSLAD, Hôpital d'Enfants, Dijon, France.
Inserm - Université Bourgogne - UMR1231 GAD, Dijon, France.
Mol Genet Genomic Med. 2025 Apr;13(4):e70096. doi: 10.1002/mgg3.70096.
Multiple molecular diagnoses (MMD) involve distinct or overlapping phenotypes. They are not so rare in the field of congenital anomalies, given an overall 3.5%-8% rate. Mainly, MMD imply distinct genotypes. Exceptionally, genotypes are linked, involving a causal CNV by itself, facing a SNV for a recessive disorder resulting in a dual diagnosis.
An unrelated couple was referred at 21 + 3 weeks of gestation for talipes equinovarus, cerebellar hypoplasia, clenched fists, elevated hemidiaphragm, and micrognathia. Chromosomal microarray and exome sequencing analyses were performed.
Both identified a pathogenic de novo 22q11.21 deletion (22q11.2del). Fetal autopsy revealed additional features (postaxial polydactyly, facial features, and abnormal lung lobulation), atypical for 22q11.2del syndrome. At the clinician's request, exome sequencing reanalysis identified a paternally inherited SCARF2 variant, in trans to the 22q11.2del causing autosomal recessive Van den Ende-Gupta syndrome. This dual diagnosis explains the entire fetus phenotype.
This is a novel case of dual diagnosis, first prenatal and second case of this ultrarare association. It reflects the crucial role of precise phenotypic description, combined with the importance of considering dual diagnosis in case of atypical clinical presentation. Finally, prenatal phenotypes remain a challenge given the paucity of available known prenatal data for most rare diseases.
ClinicalTrial.gov ID: NCT05182242.
多重分子诊断（MMD）涉及不同或重叠的表型。在先天性异常领域，它们并不罕见，总体发生率为3.5%-8%。主要而言，MMD意味着不同的基因型。例外情况是，基因型相互关联，涉及一个本身具有因果关系的拷贝数变异（CNV），同时存在一个导致隐性疾病的单核苷酸变异（SNV），从而导致双重诊断。
一对非亲属夫妇在妊娠21+3周时因马蹄内翻足、小脑发育不全、握拳、半膈肌抬高和小颌畸形前来就诊。进行了染色体微阵列和外显子组测序分析。
两者均鉴定出一个致病性的新发22q11.21缺失（22q11.2del）。胎儿尸检发现了其他特征（轴后多指畸形、面部特征和异常肺叶划分），这些特征在22q11.2del综合征中并不典型。应临床医生的要求，对外显子组测序进行重新分析，发现了一个父系遗传的SCARF2变异，与22q11.2del处于反式状态，导致常染色体隐性范登恩德-古普塔综合征。这种双重诊断解释了整个胎儿的表型。
这是一例双重诊断的新病例，首例为产前诊断，也是这种超罕见关联的第二例病例。它反映了精确表型描述的关键作用，同时也体现了在非典型临床表现情况下考虑双重诊断的重要性。最后，鉴于大多数罕见疾病的产前已知数据匮乏，产前表型仍然是一个挑战。
ClinicalTrial.gov标识符：NCT05182242。
