A novel variant of C12orf4 in a consanguineous Armenian family confirms the etiology of autosomal recessive intellectual disability type 66 with delineation of the phenotype

Abstract

Background Intellectual disability (ID) is a feature of many rare diseases caused by thousands of genes. This genetic heterogeneity implies that pathogenic variants in a specific gene are found only in a small number of patients, and difficulties arise in the definition of prevailing genotype and characteristic phenotype associated with that gene. One of such very rare disorders is autosomal recessive ID type 66 (OMIM #618221) caused by defects in C12orf4. Up to now, six families have been reported with mostly truncating variants. The spectrum of the clinical phenotype was not emphasized in previous reports, and detailed phenotype was not always available from previous patients, especially from large cohort studies. Methods Exome sequencing was performed in a consanguineous Armenian family with two affected adult brothers. Results The patients carry a novel homozygous nonsense C12orf4 variant. The integration of previous data and phenotyping of the brothers indicate that the clinical picture of C12orf4 defects involves hypotonia in infancy, rather severe ID, speech impairment, and behavioral problems such as aggressiveness, unstable mood, and autistic features. Several other symptoms are more variable and less consistent. Conclusion This rather nonsyndromic and nonspecific clinical picture implies that additional patients with C12orf4 defects will likely continue to be identified using the “genotype‐first” approach, rather than based on clinical assessment. The phenotype needs further delineation in future reports.

The novel Rab5 effector FERRY links early endosomes with the translation machinery

“…Mass spectrometry revealed the five proteins as Tbck (101 kDa), Ppp1r21 (88 kDa), C12orf4 (64 kDa), Cryzl1 (39 kDa) and Gatd1 (23 kDa) (Figure 1B). For 3 of the 5 proteins human gene mutations have been reported (Beck-Wodl et al, 2018; Bhoj et al, 2016; Chong et al, 2016; Guerreiro et al, 2016; Hancarova et al, 2019; Loddo et al, 2020; Ortiz-Gonzalez et al, 2018; Philips et al, 2017; Rehman et al, 2019; Suleiman et al, 2018; Zapata-Aldana et al, 2019). For clarity, we will refer to the novel complex as the F ive-subunit E ndosomal R ab5 and R NA/ribosome intermediar Y (FERRY) complex, with the individual subunits being designated Fy-1 – Fy-5 (Figure 1B).…”

“…Even though the FERRY complex has not previously been identified, it may play an important role in brain function. Clinical studies on patients, with a mutation in the fy-1 (tbck) or fy-2 (ppp1r21) gene, show that loss of either of these proteins severely impairs brain development and function, causing symptoms such as a mental retardation, intellectual disability, hypotonia, epilepsy, and dysmorphic facial features resulting in a premature death of the patients (Bhoj et al, 2016; Chong et al, 2016; Guerreiro et al, 2016; Hancarova et al, 2019; Loddo et al, 2020; Ortiz-Gonzalez et al, 2018; Philips et al, 2017; Suleiman et al, 2018; Zapata-Aldana et al, 2019). Different studies report the accumulation of lipofuscin the human brain and further indicate disturbances in the endocytic system (Beck-Wodl et al, 2018; Rehman et al, 2019).…”

A novel variant of C12orf4 linked to autosomal recessive intellectual disability type 66 with phenotype expansion

“…variants have been reported in seven families, who were all consanguineous. Most of the variants were truncating as two frameshift variants, 5,7 one splice donor variant, 8 two nonsense variants 11,25 and one genomic rearrangement affecting two coding-exons, 9 whereas only one variant was a missense change. 9 These variants are shown schematically in Figure 1D.…”