3.5 | Additional candidate microcephaly genes
An allele search in familial trio exome data revealed four additional candidate genes. In a patient (M-001) with primary microcephaly, we found a de novo variant (c.2123A>C;p.Tyr708Ser) in the JARID2 gene. JARID2 (jumonji and AT-rich interaction domain containing 2) is highly homologous to mouse Jumonji (Jmj). In mice, Jmj is required for normal morphogenesis of the neural tube (Takeuchi et al., 1995). This c.2123A>C variant inJARID2 was absent from the control databases.
RFX7 (regulatory factor X7) is a member of the regulatory factor X (RFX) family of transcription factors (Aftab, Semenec, Chu, & Chen, 2008). RFX7 is required for the formation of cilia in the neural tube (Manojlovic, Earwood, Kato, Stefanovic, & Kato, 2014). In one patient (M-100), we found a de novo variant (c.2727_2730dup;p.Gly911PhefsTer58) in the RFX7 gene that was absent from the control databases.
LMNB1 (lamin B1) encodes one of the two B-type lamin protein. Lamin B1, a key component of the nuclear lamina, plays an important role in brain development (Mahajani et al., 2017). A heterozygous tandem genomic duplication of LMNB1 is known to be the cause of autosomal dominant adult-onset demyelinating leukodystrophy. In one patient (M-118), we found a de novo variant (c.1091T>C;p.Leu364Pro) in this gene that was absent from the control databases.
HPRT1 (hypoxanthine guanine phosphoribosyltransferase 1) encodes hypoxanthine-guanine phosphoribosyl transferase, an enzyme involved in purine metabolism. An HPRT1 gene mutation is the cause of Lesch-Nyhan syndrome, which is an X-linked recessive disorder (Gibbs, & Caskey, 1987). In one patient (M-122), we identified a hemizygous variant (c.151C>T;p.Arg51Ter) that was inherited from his mother. This c.151C>T variant was absent from the control databases and was previously reported in a Japanese patient with Lesch-Nyhan syndrome (Fujimori, Kamatani, Nishida, Ogasawara, & Akaoka, 1990). The patient in this study did not have the clinical characteristics of that syndrome.