Patient carrying two probably damaging missense variants in HCFC1 and ATRX: one causative mutation and one modifier variant? (A) Family tree of patient.

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Patient carrying two probably damaging missense variants in HCFC1 and ATRX: one causative mutation and one modifier variant? (A) Family tree of patient APN-113: proband carries a missense mutation in HCFC1 (c.218C>T; p.Ala73Val) already reported in two patients with cblX as well as another missense variant in ATRX (c.1013C>G, p.Ser338Cys). Patient carrying two probably damaging missense variants in HCFC1 and ATRX: one causative mutation and one modifier variant? (A) Family tree of patient APN-113: proband carries a missense mutation in HCFC1 (c.218C>T; p.Ala73Val) already reported in two patients with cblX as well as another missense variant in ATRX (c.1013C>G, p.Ser338Cys). Both variants are maternally inherited, absent from the unaffected brother, but carried by the younger brother who died of sudden death at 2 months old; (B) associated predictions for the recurrent pathogenic missense mutation in HCFC164 and the possible modifier in ATRX, showing putative pathogenicity and moderate nucleotide conservation; (C) representation of HCFC1 and its domains: kelch domains (K1–K5), Fn3 (fibronectin type 3), basic domain, HCF-proteolysis repeats (HCF-pro), acidic domain and nuclear localisation signal (NLS) domain. The initial mutations involved in milder non-syndromic ID are indicated above: a regulatory variant in the 5′UTR of HCFC1 was identified by targeted massive parallel resequencing in a family with probable X-linked ID (XLID) (MRX3), which had for long remained unsolved. This variant was disrupting the functional binding site of the transcription factor YY1 within the HCFC1 promoter region, leading to an upregulation of its expression in lymphoblastoid cells.74 Subsequent screening of additional unsolved families identified one single co-segregating missense variant (c.674G>A; p.Ser225Asn) in HCFC1. The phenotype of both patients was rather mild: non-syndromic mild to moderate ID. In the bottom are indicated the mutations recently described in cblX patients64; (D) the ATRX missense variant is located close but outside of the hotspot for disease-causing missense mutations (in the zinc-finger binding domain, in green) reported in patients with ATRX mutations, in red: mutations reported independently in at least two patients. Mutations are indicated when affecting residues 1–700 (reported in OMIM, ClinVar or in75), the rest of the protein is not represented; (E) Clinical information regarding APN-113 and previous genetic explorations, including X-inactivation status in the mother. CblX patients present with the same very severe phenotype: severe ID, early infantile epilepsy, choreoathetosis, microcephaly and more variable muscular hypotonia. Three of them are reported with early death in infancy64; (F) biochemical abnormalities observed in the two affected brothers are similar to those previously observed.64 Claire Redin et al. J Med Genet 2014;51:724-736 ©2014 by BMJ Publishing Group Ltd