Identification of a Rare Case With Nagashima-Type Palmoplantar Keratoderma and 18q Deletion Syndrome via Exome Sequencing and Low-Coverage Whole-Genome Sequencing.

Qianqian Li,Xiangdong Kong,Duo Chen,Xiaofan Zhu,Jingjing Meng,Conghui Wang

doi:10.3389/fgene.2021.707411

Abstract

Nagashima-type palmoplantar keratoderma (NPPK) is characterized by non-progressive, diffuse, and cross-gradient hyperkeratosis caused by mutations in the SERPINB7 gene on chromosome 18q21.33. Chromosome 18q deletion syndrome (18q- syndrome) is a terminal deletion or microdeletion syndrome characterized by intellectual disability and congenital malformations. This paper describes an 18-year-old man with palmoplantar keratoderma and diffuse white matter abnormalities in the brain. Trio-based exome sequencing (ES) revealed a suspected mosaic compound heterozygous mutation for c.796C>T (p.Arg266∗) in exon 8 inherited from the mother and a de novo exons 4–6 deletion of SERPINB7. Additional copy number variant (CNV) analysis of the ES data indicated a heterozygous gross deletion of 18q22.3-q23. The two SERPINB7 gene variants were verified by Sanger sequencing and quantitative real-time polymerase chain reaction (qRT-PCR). Finally, low-coverage whole-genome sequencing (WGS) confirmed the 18q22.3-q23 deletion and additionally detected a mosaic 18q21.33-q22.3 deletion, together explaining NPPK and the neurological phenotypes of the proband. The gross deletion of all exons of SERPINB7 was revealed for the first time. More rarely, c.796C>T (p.Arg266∗) was likely to be mosaic, while the exon deletion was mosaic. In conclusion, the combination of multiple molecular genetic testing methods provides comprehensive informative molecular findings and promotes the diagnosis of complex diseases, as in this case.

Highlights

Nagashima-type palmoplantar keratoderma (NPPK, MIM# 615598) is the most common type of palmoplantar keratoderma in Asian populations (Kubo, 2014), with a prevalence in Japan and China of 1.2/10000 and 3.1/10000, respectively (Kubo et al, 2013)
This paper presents a rare case of NPPK and diffuse white matter abnormalities in the brain, with dual diagnosis of a suspected mosaic SERPINB7 gene mutation and an exon deletion along with 18q deletion syndrome via triobased exome sequencing (ES) and low-coverage whole-genome sequencing (WGS)
magnetic resonance imaging (MRI) images indicated that the proband had multiple abnormal signals in the bilateral frontal and parietal lobes (Figure 1D), which were similar to the previous MRI images, indicating that the abnormal areas of the white matter did not increase

Summary

Introduction

Nagashima-type palmoplantar keratoderma (NPPK, MIM# 615598) is the most common type of palmoplantar keratoderma in Asian populations (Kubo, 2014), with a prevalence in Japan and China of 1.2/10000 and 3.1/10000, respectively (Kubo et al, 2013). The clinical manifestations of NPPK include mild diffuse palmoplantar hyperkeratosis, diffuse erythema with clear boundaries. Combining Multiple Genetic Testing Methods on the dorsum of the hands, feet, forearm, and elbow, and Achilles tendon and knee. NPPK is caused by homozygous or compound heterozygous mutations in the serpin family B member 7 gene (SERPINB7) (Hannula-Jouppi et al, 2020) mapping on chromosome 18q21.33. 14 variants of SERPINB7 have been incorporated into HGMD R Professional 2021.2 (Supplementary Table 1). More than 90% of patients with NPPK carry the founder nonsense mutation c.796C>T (p.Arg266∗). Insertions, complex re-arrangements, and repeats have not yet been reported

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Results

Conclusion