Background Germline pathogenic variants in the E-cadherin gene CDH1 cause hereditary diffuse gastric cancer (HDGC), which is an autosomal dominant cancer syndrome, accounting for 1–3% of all gastric cancers. HDGC harboring a CDH 1 variant is extremely rare in Japan. Method In this study we report the clinical courses of three cases with HDGC from a single Japanese family. Results The proband exhibited advanced and metastatic gastric cancer, and was found to have a previously reported heterozygous frameshift variant in CDH1 (NM_004360.3:c.1009_1010del:p.Ser337Phefs*12). Five at-risk relatives underwent presymptomatic molecular testing after careful genetic counseling, and three were molecularly diagnosed as positive for the variant. Esophagogastroduodenoscopy was performed in these relatives revealing abnormal small pale mucosal patches, small ulcerative lesion and no abnormal findings. Moreover, random and targeted biopsies were compatible with pathological diagnosis of HDGC in the three cases, all of which underwent total prophylactic gastrectomy. Conclusion It is critical for the assessment and management of HDGC patients to be actively offered a multidisciplinary and familial-oriented approach. Notably, genetic screening in suspected individuals and familial members is a determining piece for a higher detection rate and the identification of clinical relevant mutations in both low and high-incidence gastric cancer countries.

Background; Germline pathogenic variants in the E-cadherin gene CDH1 cause hereditary diffuse gastric cancer (HDGC), which is an autosomal dominant cancer syndrome, accounting for 1% of all gastric cancers. HDGC harboring a CDH 1 variant is extremely rare in Japan. Method; Here, we describe four cases of HDGC in a single Japanese family. Results; The proband exhibited advanced and metastatic gastric cancer, and was found to have a previously reported heterozygous frameshift variant in CDH1 (NM_004360.3:c.1009_1010del:p.Ser337Phefs*12). Five at-risk relatives underwent presymptomatic molecular testing after careful genetic counseling, and three were molecularly diagnosed as positive for the variant. Esophagogastroduodenoscopy was performed in three relatives, which revealed abnormal small pale mucosal patches, small ulcerative lesion, and no abnormal findings, respectively. Random and targeted biopsies were compatible with the pathological diagnosis of HDGC. They underwent total gastrectomy and Roux-en-Y reconstruction with D2 lymph node dissection. Conclusion; In the management of HDGC, multidisciplinary and family-oriented approaches are critical, including genetic analysis of CDH1 variants in the proband, presymptomatic diagnosis of at-risk relatives through careful genetic counseling, and random biopsy-based surgery or prophylactic total gastrectomy.

We encountered a 37-year-old Japanese man with KIF1A-associated neurological disorder (KAND) who exhibited motor developmental delay, intellectual disability, and slowly progressive cerebellar ataxia, hypotonia, and optic neuropathy. Pyramidal tract signs were evident late in this case. At 30 years old, the patient developed a neurogenic bladder. A molecular diagnosis revealed a uniallelic missense de novo variant (p.L278P) of KIF1A. Serial neuroradiological studies revealed atrophy of the cerebellum at an early age, and cerebral hemisphere atrophy progressed slowly over a 22-year observation period. Our study suggests that the primary etiology of KAND may be acquired, long-standing neurodegeneration rather than congenital hypoplasia.