RESUMO
Primary familial brain calcification (PFBC) is a rare neurological disorder. Mutations in five genes (SLC20A2, PDGFRB, PDGFB, XPR1, and MYORG) have been linked to PFBC. Here, we used SYBR green-based real-time quantitative polymerase chain reaction (PCR) assay and denaturing high-performance liquid chromatography analysis to detect copy number variants (CNVs) in 20 unrelated patients with PFBC, negatively sequenced for the five known genes. We identified three deletions in SLC20A2, including a large de novo full gene deletion and two exonic deletions confined to exon 2 and exon 6, respectively. Subsequent linked-read whole-genome sequencing of the patient with the large deletion showed a 1.7 Mb heterozygous deletion which removed the entire coding regions of SLC20A2 as well as 21 other genes. In the family with a deletion of exon 6, a missense variant of uncertain significance (SLC20A2: p.E267Q) also co-segregated with the disease. Functional assay showed the deletion could result in significantly impaired phosphate transport, whereas the p.E267Q variant did not. Our results confirm that deletion in SLC20A2 is a causal mechanism for PFBC and highlight the importance of functional study for classifying a rare missense variant as (likely) pathogenic.
Assuntos
Doenças dos Gânglios da Base/diagnóstico , Doenças dos Gânglios da Base/genética , Calcinose/diagnóstico , Calcinose/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Deleção de Sequência , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Adolescente , Adulto , Idoso , Alelos , Criança , Feminino , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Linhagem , Fenótipo , Análise de Sequência de DNA , Receptor do Retrovírus Politrópico e Xenotrópico , Adulto JovemRESUMO
BACKGROUND: Mechanical thrombectomy (MT) has been proved to be a highly effective therapy to treat acute ischemic stroke due to large vessel occlusion. Often, the ischemic core extent on baseline imaging is an important determinant for endovascular treatment eligibility. However, computed tomography (CT) perfusion (CTP) or diffusion-weighted imaging may overestimate the infarct core on admission and, consequently, smaller infarct lesions called "ghost infarct cores." OBSERVATIONS: A 4-year-old, previously healthy boy presented with acute-onset, right-sided weakness and aphasia. Fourteen hours after the onset of symptoms, the patient presented with a National Institutes of Health Stroke Scale (NIHSS) score of 22, and magnetic resonance angiography demonstrated a left middle cerebral artery occlusion. MT was not considered because of a large infarct core (infarct core volume: 52 mL; mismatch ratio 1.6 on CTP). However, multiphase CT angiography indicated good collateral circulation, which encouraged MT. Complete recanalization was achieved via MT at 16 hours after the onset of symptoms. The child's hemiparesis improved. Follow-up magnetic resonance imaging was nearly normal and showed that the baseline infarct lesion was reversible, in agreement with neurological improvement (NIHSS score 1). LESSONS: The selection of pediatric stroke with a delayed time window guided by good collateral circulation at baseline seems safe and efficacious, which suggests a promising value of vascular window.