HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients

Abstract

Whole-gene duplications and missense variants in the HUWE1 gene (NM_031407.6) have been reported in association with intellectual disability (ID). Increased gene dosage has been observed in males with non-syndromic mild to moderate ID with speech delay. Missense variants reported previously appear to be associated with severe ID in males and mild or no ID in obligate carrier females. Here, we report the largest cohort of patients with HUWE1 variants, consisting of 14 females and 7 males, with 15 different missense variants and one splice site variant. Clinical assessment identified common clinical features consisting of moderate to profound ID, delayed or absent speech, short stature with small hands and feet and facial dysmorphism consisting of a broad nasal tip, deep set eyes, epicanthic folds, short palpebral fissures, and a short philtrum. We describe for the first time that females can be severely affected, despite preferential inactivation of the affected X chromosome. Three females with the c.329 G > A p.Arg110Gln variant, present with a phenotype of mild ID, specific facial features, scoliosis and craniosynostosis, as reported previously in a single patient. In these females, the X inactivation pattern appeared skewed in favour of the affected transcript. In summary, HUWE1 missense variants may cause syndromic ID in both males and females.

Fig. 1

Pedigrees of families with maternally inherited HUWE1 variants. Red arrow indicates the proband; +, hemizygous status; +/-, heterozygous status, -/-, wt. Numbers in brackets indicate the XCI pattern in female carriers. (Color figure online)

Fig. 2

Schematic representation of HUWE1 protein with identified variants. (Refseq: NM_031407.6, NCBI Protein Reference Sequence: NP_113584.3). The amino-acid borders of the described HUWE1 domains are noted. Previously published variants are shown on the left and variants in the present cohort on the right. Only rare non-synonymous and splice site variants are presented. Male patients are in blue and female in red. Number in parenthesis indicates recurrent variants describing number of families reported for the variant. *Females with schizophrenia as indication for WES with de novo HUWE1 missense changes. DUF domain of unknown function; UBA ubiquitin-associated; WWE tryptophan tryptophan glutamate; HECT homologous to the E6-AP Carboxyl Terminus. (Color figure online)

Fig. 3

X inactivation patterns in female patients in varying tissues and associated RNA expression analysis. cDNA sequencing was used to determine which allele was preferentially expressed; the green colour indicated the expression pattern of the wild-type allele and the red colour indicated the expression pattern of the mutated allele. The numbers superimposed on bars represent XCI in the specified tissue. ^*P2 analysed by Taylor et al. In P7, XCI was non-informative due to homozygous AR-alleles, but wt-allele exclusively expressed in blood. In P11, cDNA analysis was performed in one tissue demonstrating preferential expression of the wild-type allele. This was assumed to be true for both tissues. (Color figure online)

Fig. 4

Facial and limb features of individuals with HUWE1 variants, frontal and lateral views. a Facial features of all but two patients in the cohort. Patient numbers correspond to those in the text and tables. Detailed description of facial phenotype can be found in Table 1. Note the particular phenotype in P1 to P3 (carrying the same de novo c.329 G > A p.Arg110Gln variant) consisting of a flat face, prominent eyes and a small nose, compared with other patients (P4–P20) who present with deep set eyes, epicanthic folds, blepharophimosis, broad nasal tip and thin upper lip. The facial shape seems to evolve with time, from round face with full cheeks to long face, as seen in P6, P19 and P20. b Skeletal features include small hands, short distal phalanges and short nails in P1–P3, clinodactyly of 5th fingers, small nails, short metatarsals and 3rd–5th toes in P1 and P2, 2–3 syndactyly in P1 and P3. Tapering of fingers and puffy hands are shown in P8, and overlapping toes in P16 and P17. (Color figure online)