Further delineation of HIDEA syndrome

Abstract

Recently, the genetic cause of HIDEA syndrome (hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities) was identified as biallelic pathogenic variants in P4HTM, which encodes an atypical member of the prolyl 4-hydroxylases (P4Hs) family of enzymes. We report seven patients from four new families in whom HIDEA was only diagnosed after whole-exome sequencing (WES) revealed novel disease-causing variants in P4HTM. We note the variable phenotypic expressivity of the syndrome except for cognitive impairment/developmental delay, and hypotonia, which seem to be consistent findings. One patient only presented with hypotonia, developmental delay, and abnormal eye movements, which highlights the challenge in diagnosing milder cases with this new syndrome. Other notable features include mild facial dysmorphism, obesity, and brain dysmyelination and atrophy. We conclude that HIDEA is a highly variable syndrome and suspect that a large fraction of patients will be diagnosed via reverse phenotyping after recessive P4HTM variants are identified by agnostic genomic sequencing assays.

Biallelic P4HTM variants associated with HIDEA syndrome and mitochondrial respiratory chain complex I deficiency

“…Table 1 [ 5 , 8 , 9 ] summarises the findings in the previously reported cases and phenotypic overlap with the patient we report. The predominance of males is presumed to be by chance, given the autosomal recessive nature of the condition.…”

“…a temporal disc pallor. b using data from case descriptions due to discrepancies in Table 1 from Maddirevula et al [ 9 ].…”

“…Of note, the P4HTM NM_177938.2 c.[1073G>A] variant has been reported in two Finnish families and appears to have an allele frequency 20 times higher in the Finnish population than non-Finnish Europeans in gnomAD [ 5 , 8 ]. The P4HTM NM_177938.2 c.[949delG] variant has now been reported in two Syrian families [ 5 , 9 ] suggesting a possible founder effect.…”

“…[949delG] variant has now been reported in two Syrian families [5,9] suggesting a possible founder effect.…”

“…Report Current Rahikkala et al [5] and Kaasinen et al [8] Maddirevula et al [9] Total (%) using data from case descriptions due to discrepancies in Table 1 from Maddirevula et al [9].…”