ZNF335 was first reported in 2012 as a causative gene for microcephaly. Because only 1 consanguineous pedigree has ever been reported, the key clinical features associated with ZNF335 mutations remain unknown. In this article, we describe another family harboring ZNF335 mutations. The female proband was the first child of nonconsanguineous Japanese parents. At birth, microcephaly was absent; her head circumference was 32.0 cm (−0.6 SD). At 3 months, microcephaly was noted, (head circumference, 34.0 cm [−4.6 SD]). Brain MRI showed invisible basal ganglia, cerebral atrophy, brainstem hypoplasia, and cerebellar atrophy. At 33 months, (head circumference, 41.0 cm [−5.1 SD]), she had severe psychomotor retardation. After obtaining informed consent from her parents, we performed exome sequencing in the proband and identified 1 novel and 1 known mutation in ZNF335, namely, c.1399T>C (p.C467R) and c.1505A>G (p.Y502C), respectively. The mutations were individually transmitted by her parents, indicating that the proband was compound heterozygous for the mutations. Her brain imaging findings, including invisible basal ganglia, were similar to those observed in the previous case with ZNF335 mutations. We speculate that invisible basal ganglia may be the key feature of ZNF335 mutations. For infants presenting with both microcephaly and invisible basal ganglia, ZNF335 mutations should be considered as a differential diagnosis.
Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 are responsible for a large proportion of familial breast cancer cases, and therefore, BRCA1 and BRCA2 genetic testing has become increasingly common in clinical practice. However, variants of uncertain significance (VUS) have been detected in 16.3% of Japanese patients suspected of having hereditary breast and ovarian cancers. The clinical importance of VUS is unknown, and their incidence has led to issues in risk counseling, assessment and treatment of cancer patients. In the present study, we performed functional analyses of two VUS in BRCA1, A1752G and Y1853C that were detected in two independent breast cancer patients who were suspected of having hereditary breast cancer. Segregation analysis revealed that Y1853C, but not A1752G, was cosegregated in affected family members. Conservation, transcription and structure analyses also supported the pathogenic potential of Y1853C. Detailed segregation and in silico and in vitro analyses will enhance our understanding of VUS and improve the management of cancer patients and their families.
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