Identification of Mutations in TOP3A
In ongoing work to identify genes associated with microcephalic dwarfism, whole-exome sequencing (WES) was performed on subject P1, who had significant microcephaly and short stature (−5.7 and −4.4 standard deviations [SD], respectively). This identified the homozygous frameshift mutation c.2718del (p.Thr907LeufsTer101) (GenBank: NM_004618.4) in TOP3A in chromosomal region 17p11.2. After interrogation of other cohorts and clinical contacts made through GeneMatcher,31 we subsequently ascertained a further nine individuals from seven families affected by biallelic deleterious TOP3A variants that had also been discovered by WES (Table 1). All variants identified were validated by Sanger capillary sequencing, and all parents were confirmed to be heterozygous carriers. Aside from the c.2718del variant (minor allele frequency = 0.00041%), none of the other variants were reported in GnomAD.33 Notably, four of the families from the United Arab Emirates, Syria, and Saudi Arabia (F2, F4, F6, and F7), were homozygous for the same variant.
Table 1 Identified TOP3A and RMI1 Variants Associated with Microcephalic Dwarfism Nomenclature is according to transcript GenBank: NM_004618.4 for TOP3A and GenBank: NM_004618.4 and NM_024945.2 for RMI1. a Close to donor splice site of exon 10. b Previously reported individual with adult-onset mitochondrial disease.32