Identification of C12orf4 as a gene for autosomal recessive intellectual disability

Abstract

Intellectual disability (ID) is a major health problem in our society. Genetic causes of ID remain unknown because of its vast heterogeneity. Here we report two Finnish families and one Dutch family with affected individuals presenting with mild to moderate ID, neuropsychiatric symptoms and delayed speech development. By utilizing whole exome sequencing (WES), we identified a founder missense variant c.983T>C (p.Leu328Pro) in seven affected individuals from two Finnish consanguineous families and a deletion c.799_1034-429delinsTTATGA (p.Gln267fs) in one affected individual from a consanguineous Dutch family in the C12orf4 gene on chromosome 12. Both the variants co-segregated in the respective families as an autosomal recessive trait. Screening of the p.Leu328Pro variant showed enrichment in the North Eastern sub-isolate of Finland among anonymous local blood donors with a carrier frequency of 1:53, similar to other disease mutations with a founder effect in that region. To date, only one Arab family with a three affected individuals with a frameshift insertion variant in C12orf4 has been reported. In summary, we expand and establish the clinical and mutational spectrum of C12orf4 variants. Our findings implicate C12orf4 as a causative gene for autosomal recessive ID.

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).…”

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

“…Both our patients showed macrocephaly but this feature may be familial (HC of their unaffected father and mother was 58.5 cm (>99th centile, +2.4 SD ) and 56 cm (94th centile), respectively, while the unaffected youngest brother had HC of 54 cm (90th centile)). Also the previous patients with C12orf4 defects from whom sufficient clinical information was available did not show macrocephaly (Alazami et al, ; Maddirevula et al, ; Philips et al, ). Taken together, this rather nonsyndromic nature of the condition and its nonspecific clinical picture imply that additional patients will likely continue to be identified using the “genotype‐first” approach rather than based on clinical assessment.…”

“…Up to now, homozygous C12orf4 variants have been found in patients from six families including one large Finnish pedigree. Most of the variants were truncating: one nonsense variant (Reuter et al, ), two frameshift variants (Alazami et al, ; Harripaul et al, ), one splice donor variant (Maddirevula et al, ), and one genomic rearrangement affecting two coding exons (Philips et al, ); and only one variant was a missense change (Philips et al, ) (Table ). The nonsense C12orf4 variant identified in the current family fits the prevailing variant spectrum; in fact, the variant is the most 5´ located truncating change among all variants (Figure h), and its effect may be among the most deleterious.…”

“…The C12orf4 gene was first suggested as a possible candidate gene for ARID in one Arab family in 2015 (Alazami et al, ). Clinical pictures of additional patients from a large Finnish pedigree and a Dutch family (Philips et al, ), and from a Turkish family (Reuter et al, ) were published later. Based on these reports the condition was listed in OMIM as autosomal recessive ID type 66 (#618221).…”

A novel conserved family of Macro-like domains—putative new players in ADP-ribosylation signaling

“…Recent findings of two independent groups from Saudi Arabia and Europe analyzing multiplex consanguineous families with members suffering from intellectual disability (ID) using whole-exome sequencing implicate the mysterious C12ORF4 as a causative gene for autosomal ID, an important health problem in society (Alazami et al, 2015; Philips et al, 2017). Genetic causes of ID still remain poorly explained because of its vast heterogeneity (Anazi et al, 2017).…”