Introduction: Peroxisome biogenesis disorders (PBDs) encompass a group of diseases marked by clinical and genetic heterogeneity. Phenotypes linked to PBDs include Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease (IRD), rhizomelic chondrodysplasia punctata type 1, and Heimler syndrome. PBD phenotypes manifest through hypotonia, developmental delay, facial dysmorphism, seizures, liver dysfunction, sensorineural hearing loss, and retinal dystrophy. Methods: The proband underwent comprehensive clinical evaluation, followed by whole-exome sequencing (WES) coupled with copy number analysis (CNV), aimed at identifying potential disease-causing variants aligning with the observed phenotype. Results: Our findings detail an individual exhibiting developmental delay, hearing loss, visual impairment, hepatomegaly, and splenomegaly, attributed to a biallelic deletion of exon 4 in the PEX26 gene. The WES analysis of the index case did not uncover any pathogenic/likely pathogenic single-nucleotide variations that could account for the observed clinical findings. However, the CNV data derived from WES revealed a homozygous deletion in exon 4 of the PEX26 gene (NM_001127649.3), providing a plausible explanation for the patient’s clinical features. The exon 4 region of PEX26 encodes the transmembrane domain of the protein. The transmembrane domain plays a crucial role in anchoring the protein within lipid bilayers, and its absence can disrupt proper localization and functioning. As a result, this structural alteration may impact the protein’s ability to facilitate essential cellular processes related to peroxisome biogenesis and function. Conclusion: The index patient, which presented with hearing loss, retinal involvement and hepatic dysfunction in adolescence age, has atypical clinical course that can be considered unusual for Zellweger syndrome (ZS) and IRD phenotypes, and its rare genotypic data (in-frame single exon deletion) expands the PBD disease spectrum. This study revealed for the first time that PEX26 protein transmembrane domain loss exhibits an unusual course with clinical findings of IRD and ZS phenotypes. WES studies, incorporating CNV analyses, empower the identification of novel genetic alterations in genes seldom associated with gross deletion/duplication variations, such as those in the PEX26 gene. This not only enhances diagnostic rates in rare diseases but also contributes to broadening the spectrum of causal mutations.

1.
Furuki
S
,
Tamura
S
,
Matsumoto
N
,
Miyata
N
,
Moser
A
,
Moser
HW
, et al
.
Mutations in the Peroxin Pex26p responsible for peroxisome biogenesis disorders of complementation group 8 impair its stability, peroxisomal localization, and interaction with the Pex1p x Pex6p complex
.
J Biol Chem
.
2006
;
281
(
3
):
1317
23
.
2.
Fujiki
Y
,
Abe
Y
,
Imoto
Y
,
Tanaka
AJ
,
Okumoto
K
,
Honsho
M
, et al
.
Recent insights into peroxisome biogenesis and associated diseases
.
J Cell Sci
.
2020
;
133
(
9
):
jcs236943
.
3.
Tanaka
AJ
,
Okumoto
K
,
Tamura
S
,
Abe
Y
,
Hirsch
Y
,
Deng
L
, et al
.
A newly identified mutation in the PEX26 gene is associated with a milder form of Zellweger spectrum disorder
.
Cold Spring Harb Mol Case Stud
.
2019
;
5
(
1
):
a003483
.
4.
Semenova
NA
,
Kurkina
MV
,
Marakhonov
AV
,
Dadali
EL
,
Taran
NN
,
Strokova
TV
.
A novel mutation in the PEX26 gene in a family from Dagestan with members affected by Zellweger spectrum disorder
.
Mol Genet Metab Rep
.
2021
;
27
:
100754
.
5.
Kim
YJ
,
Abe
Y
,
Kim
YJ
,
Fujiki
Y
,
Kim
JW
.
Identification of a homozygous PEX26 mutation in a heimler syndrome patient
.
Genes
.
2021
;
12
(
5
):
646
.
6.
Gao
FJ
,
Hu
FY
,
Xu
P
,
Qi
YH
,
Li
JK
,
Zhang
YJ
, et al
.
Expanding the clinical and genetic spectrum of Heimler syndrome
.
Orphanet J Rare Dis
.
2019
;
14
(
1
):
290
.
7.
Richards
S
,
Aziz
N
,
Bale
S
,
Bick
D
,
Das
S
,
Gastier-Foster
J
, et al
.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of medical genetics and genomics and the association for molecular pathology
.
Genet Med
.
2015
;
17
(
5
):
405
24
.
8.
Royer-Bertrand
B
,
Cisarova
K
,
Niel-Butschi
F
,
Mittaz-Crettol
L
,
Fodstad
H
,
Superti-Furga
A
.
CNV detection from exome sequencing data in routine diagnostics of rare genetic disorders: opportunities and limitations
.
Genes
.
2021
;
12
(
9
):
1427
.
9.
Varadi
M
,
Anyango
S
,
Deshpande
M
,
Nair
S
,
Natassia
C
,
Yordanova
G
, et al
.
AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models
.
Nucleic Acids Res
.
2022
;
50
(
D1
):
439
44
.
10.
Lomize
AL
,
Todd
SC
,
Pogozheva
ID
.
Spatial arrangement of proteins in planar and curved membranes by PPM 3.0
.
Protein Sci
.
2022
;
31
(
1
):
209
20
.
11.
Hoepfner
D
,
Schildknegt
D
,
Braakman
I
,
Philippsen
P
,
Tabak
HF
.
Contribution of the endoplasmic reticulum to peroxisome formation
.
Cell
.
2005
;
122
(
1
):
85
95
.
12.
Matsumoto
N
,
Tamura
S
,
Furuki
S
,
Miyata
N
,
Moser
A
,
Shimozawa
N
, et al
.
Mutations in novel Peroxin gene PEX26 that cause peroxisome-biogenesis disorders of complementation group 8 provide a genotype-phenotype correlation
.
Am J Hum Genet
.
2003
;
73
(
2
):
233
46
.
13.
He
Y
,
Lin
SB
,
Li
WX
,
Yang
L
,
Zhang
R
,
Chen
C
, et al
.
PEX26 gene genotype-phenotype correlation in neonates with Zellweger syndrome
.
Transl Pediatr
.
2021
;
10
(
7
):
1825
33
.
You do not currently have access to this content.