Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome)

Abstract

PurposeA new syndrome with hypotonia, intellectual disability, and eye abnormalities (HIDEA) was previously described in a large consanguineous family. Linkage analysis identified the recessive disease locus, and genome sequencing yielded three candidate genes with potentially pathogenic biallelic variants: transketolase (TKT), transmembrane prolyl 4-hydroxylase (P4HTM), and ubiquitin specific peptidase 4 (USP4). However, the causative gene remained elusive.MethodsInternational collaboration and exome sequencing were used to identify new patients with HIDEA and biallelic, potentially pathogenic, P4HTM variants. Segregation analysis was performed using Sanger sequencing. P4H-TM wild-type and variant constructs without the transmembrane region were overexpressed in insect cells and analyzed using sodium dodecyl sulfate–polyacrylamide gel electrophoresis and western blot.ResultsFive different homozygous or compound heterozygous pathogenic P4HTM gene variants were identified in six new and six previously published patients presenting with HIDEA. Hypoventilation, obstructive and central sleep apnea, and dysautonomia were identified as novel features associated with the phenotype. Characterization of three of the P4H-TM variants demonstrated yielding insoluble protein products and, thus, loss-of-function.ConclusionsBiallelic loss-of-function P4HTM variants were shown to cause HIDEA syndrome. Our findings enable diagnosis of the condition, and highlight the importance of assessing the need for noninvasive ventilatory support in patients.

Further delineation of HIDEA syndrome

“…In addition, anesthesia-related risk for this imaging procedure should be carefully considered in these patients given their hypoventilation that may or may not be apparent clinically. We confirm lack of renal impairment in any of our patients in contrast to the ily 3 was previously reported in another Syrian family raising the possibility that this is a founder variant (Rahikkala et al, 2019).…”

“…Although the facial features are not distinct, the unusual association of dysautonomia, strabismus, and hypoventilation should facilitate the diagnosis of this form of intellectual disability and developmental delay. As noted by Rahikkala et al (2019), the expressivity of the different phenotypic components of HIDEA is variable in the four families reported here (Table 1). The index patient in Family 1 did not have hypoventilation, dysautonomia or epilepsy.…”

“…HIDEA was initially defined on the basis of a single Finnish family, and it was through the phenotypic overlap with other families that the link to P4HTM was unequivocally established (Kaasinen et al, 2014;Rahikkala et al, 2019) disconjugate eye movement and poor vision. Interestingly, obesity, which was observed in approximately 30% of the original cohort was also seen in some of our patients, and while bone age was not specifically investigated [advanced bone age was reported in one patient by (Rahikkala et al, 2019)], we note that there was tendency to overgrowth in some patients. Brain MRI appears to be of little diagnostic value in this syndrome given the lack of characteristic abnormalities apart from the occasionally observed nonspecific dysmyelination and mild brain atrophy.…”

“…HIDEA was initially defined on the basis of a single Finnish family, and it was through the phenotypic overlap with other families that the link to P4HTM was unequivocally established (Kaasinen et al, 2014; Rahikkala et al, 2019). Although the facial features are not distinct, the unusual association of dysautonomia, strabismus, and hypoventilation should facilitate the diagnosis of this form of intellectual disability and developmental delay.…”

“…The acronym HIDEA (Hypotonia‐Intellectual Disability‐Eye Abnormalities) was proposed and although a candidate missense variant in P4HTM was identified, it was in linkage disequilibrium with two other candidate variants so no definitive causal link could be established (Kaasinen et al, 2014). However, subsequent identification of additional patients with different biallelic P4HTM variants and the demonstration of the deleterious nature of these variants on the protein solubility confirmed the P4HTM ‐HIDEA link and the acronym was expanded to also include hypoventilation, dysautonomia and epilepsy (Rahikkala et al, 2019). Here, we describe four previously unpublished families with HIDEA to further delineate the clinical phenotype.…”