Abstract:

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder caused by survival motor neuron gene mutations. Variant forms of SMA accompanied by additional clinical presentations have been classified as atypical SMA and are thought to be caused by variants in as yet unidentified causative genes. Here, we presented the clinical findings of two siblings with an SMA variant followed by progressive cerebral atrophy, and the results of whole-exome sequencing analyses of the family quartet that was performed to identify potential causative variants. We identified two candidate homozygous missense variants, R942Q in the tubulin-folding cofactor D (TBCD) gene and H250Q in the bromo-adjacent homology domain and coiled-coil containing 1 (BAHCC1) gene, located on chromosome 17q25.3 with an interval of 1.4 Mbp. The in silico analysis of both variants suggested that TBCD rather than BAHCC1 was likely the pathogenic gene (TBCD sensitivity, 0.68; specificity, 0.97; BAHCC1 sensitivity, 1.00; specificity, 0.00). Thus, our results show that TBCD is a likely novel candidate gene for atypical SMA with progressive cerebral atrophy. TBCD is predicted to have important functions on tubulin integrity in motor neurons as well as in the central nervous system.

日本語要旨:

脊髄性筋萎縮症 (SMA) はSMN遺伝子変異により引き起こされる常染色体劣性遺伝性疾患である。通常のSMAでは認めない臨床所見を伴うvariant formのSMAは非典型的SMAに分類されるが、原因遺伝子はわかっていない。今回、我々は、進行性の大脳萎縮を伴う非典型的SMAの兄弟例において、非罹患家族も含めて全エクソームシーケンス解析を行い、17番染色体q25.3に存在する2つのホモ接合性バリアント、tubulin-folding cofactor D (TBCD)遺伝子のR942Q、bromo-adjacent homology domain and coiled-coil cantaining 1 (BAHCC1)遺伝子のH250Q、を原因遺伝子候補として見出した。コンピューターを用いた解析では、TBCD遺伝子のバリアントがより病的な変異である可能性が高いと考えられた。TBCDは、運動ニューロンや中枢神経系のtubulin integrityに重要な役割を果たしていると予想されるが、進行性の大脳萎縮を伴う非典型的SMAの新規原因遺伝子の可能性がある。