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Targeted sequencing approach to identify genetic mutations in Nasu-Hakola disease
Jun-Ichi Satoh1, Motoaki Yanaizu1, Youhei Tosaki1
1Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Tokyo, Japan.
Insights
Nasu-Hakola disease (NHD) genetic diagnosis is improved by targeted next-generation sequencing (NGS). This method precisely identifies TYROBP or TREM2 mutations, aiding in accurate diagnosis of this rare neurological and bone disorder.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder.
- It is characterized by sclerosing leukoencephalopathy and multifocal bone cysts.
- Causative mutations are found in TYROBP (DAP12) or TREM2 genes, forming a critical signaling complex.
Purpose of the Study:
- To evaluate targeted next-generation sequencing (NGS) as a diagnostic tool for Nasu-Hakola disease (NHD).
- To precisely identify genetic mutations in TYROBP and TREM2 responsible for NHD.
- To assess the efficiency of targeted sequencing in diagnosing NHD cases.
Main Methods:
- Resequencing of TYROBP and TREM2 genes using the TruSight One Sequencing Panel.
- Analysis of seven NHD cases with known molecular diagnoses and two control subjects.
- Comparison of targeted sequencing results with Sanger sequencing.
Main Results:
- Targeted sequencing identified homozygous TYROBP or TREM2 variants in all seven NHD cases.
- Specific mutations included a frameshift mutation in TYROBP (c.141delG), a missense mutation in TYROBP (c.2T>C), and a splicing mutation in TREM2 (c.482+2T>C).
- No causative variants were detected in control subjects, and results correlated with Sanger sequencing.
Conclusions:
- Targeted sequencing is a highly effective and precise method for identifying genetic mutations in NHD.
- This approach facilitates comprehensive molecular diagnosis of Nasu-Hakola disease.
- NGS technology significantly advances the diagnostic capabilities for rare genetic disorders like NHD.
Abstract:
Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder characterized by sclerosing leukoencephalopathy and multifocal bone cysts, caused by a loss-of-function mutation of either TYROBP (DAP12) or TREM2. TREM2 and DAP12 constitute a receptor/adaptor signaling complex expressed exclusively on osteoclasts, dendritic cells, macrophages, and microglia. Premortem molecular diagnosis of NHD requires genetic analysis of both TYROBP and TREM2, in which 20 distinct NHD-causing mutations have been reported. Due to genetic heterogeneity, it is often difficult to identify the exact mutation responsible for NHD. Recently, the revolution of the next-generation sequencing (NGS) technology has greatly advanced the field of genome research. A targeted sequencing approach allows us to investigate a selected set of disease-causing genes and mutations in a number of samples within several days. By targeted sequencing using the TruSight One Sequencing Panel, we resequenced genetic mutations of seven NHD cases with known molecular diagnosis and two control subjects. We identified homozygous variants of TYROBP or TREM2 in all NHD cases, composed of a frameshift mutation of c.141delG in exon 3 of TYROBP in four cases, a missense mutation of c.2T>C in exon 1 of TYROBP in two cases, or a splicing mutation of c.482+2T>C in intron 3 of TREM2 in one case. The results of targeted resequencing corresponded to those of Sanger sequencing. In contrast, causative variants were not detected in control subjects. These results indicate that targeted sequencing is a useful approach to precisely identify genetic mutations responsible for NHD in a comprehensive manner.
