A New Case of de novo Variant c.892C>T (p.Arg298Trp) in NACC1: A First Case Report From China

Abstract

Background: The nucleus accumbens associated 1 (NACC1) gene is a transcription factor member of the BTB/POZ family. A de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1 may define a syndrome characterized by intellectual disability, infantile epilepsy, congenital cataract, and feeding difficulties.Case Presentation: We report a new case with a neurodevelopmental disorder characterized by severe intellectual disability, infantile epilepsy, congenital cataract, and feeding difficulties. Brain MRI reveals brain dysplasia. We observe a de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1 gene in this case. Now, the child regularly goes to the hospital for rehabilitation training (once a month). Sodium Valproate (10 mg/kg/day) and Clobazam (10 mg/kg/day) are used in the treatment of epilepsy. A total of three articles were screened, and two papers were excluded. The search revealed one article related to a syndrome caused by a de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1; they screened the main clinical features of eight cases of a syndrome, which were summarized and analyzed.Conclusions: The NACC1 gene is a member of the BTB/POZ family of transcription factors. A de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1 may define a syndrome characterized by intellectual disability, infantile epilepsy, congenital cataract, and feeding difficulties. At present, there is no effective cure. In the future, we need more cases to determine the phenotype–genotype correlation of NACC1 variants. Many questions remain to be answered, and many challenges remain to be faced. Future transcriptional studies may further clarify this rare, recurrent variant, and could potentially lead to targeted therapies.

An intellectual-disability-associated mutation of the transcriptional regulator NACC1 impairs glutamatergic neurotransmission

“…This led to the yet untested proposition that Nacc1 regulates synapse function in neurons. In accord with this, a heterozygous de novo mutation in the gene encoding NACC1 (NACC1, NM_052876.3: c.892C > T, NP_443108.1; p.Arg298Trp, referred here as NACC1-R298W for simplification purpose) was recently identified by whole-exome sequencing in eight unrelated individuals with a neurodevelopmental disorder characterized by severe intellectual and developmental disability, epilepsy, and abnormal brain morphology (Schoch et al, 2017;Lyu et al, 2021). These observations show that the pathogenic NACC1 mutant protein perturbs brain development and neural function.…”

Hyperkinetic Movement Disorder Caused by the Recurrent c.892C>T NACC1 Variant

“…Recently, a de novo heterozygous NACC1 (nucleus accumbens‐associated 1), HUGO Gene Nomenclature Committee (HGNC) Identifier HGNC:20967, c.892C>T (NM_052876.4; NP_443108.1: p.Arg298Trp) variant has been described in nine patients with infantile onset epilepsy, postnatal microcephaly, severe to profound intellectual disability, bilateral cataracts, and hyperkinetic movements including hand stereotypies, chorea, and dystonia. 9 , 10 , 11 Furthermore, one of these patients also exhibited combined oxidative phosphorylation (OXPHOS) deficiency. 9 NACC1 encodes nucleus accumbens‐associated protein 1 (NACC1), which is also known as BTB/POZ domain‐containing protein 14B (BTBD14B), and it is a multifunctional protein that has been shown to act as a versatile transcription factor, but it also plays a role in protein turnover.…”

“…Recently, a de novo heterozygous NACC1 (nucleus accumbens‐associated 1), HUGO Gene Nomenclature Committee (HGNC) Identifier HGNC:20967, c.892C>T (NM_052876.4; NP_443108.1: p.Arg298Trp) variant has been described in nine patients with infantile onset epilepsy, postnatal microcephaly, severe to profound intellectual disability, bilateral cataracts, and hyperkinetic movements including hand stereotypies, chorea, and dystonia 9–11 . Furthermore, one of these patients also exhibited combined oxidative phosphorylation (OXPHOS) deficiency 9 .…”