Genetic insights into PHARC syndrome: identification of a novel frameshift mutation in ABHD12
BMC Medical Genomics volume 16, Article number: 235 (2023)
Mutations in ABHD12 (OMIM: 613,599) are associated with polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) syndrome (OMIM: 612674), which is a rare autosomal recessive neurodegenerative disease. PHARC syndrome is easily misdiagnosed as other neurologic disorders, such as retinitis pigmentosa, Charcot-Marie-Tooth disease, and Refsum disease, due to phenotype variability and slow progression. This paper presents a novel mutation in ABHD12 in two affected siblings with PHARC syndrome phenotypes. In addition, we summarize genotype-phenotype information of the previously reported patients with ABHD12 mutation.
Following a thorough medical evaluation, whole-exome sequencing was done on the proband to look for potential genetic causes. This was followed by confirmation of identified variant in the proband and segregation analysis in the family by Sanger sequencing. The variants were interpreted based on the American College of Medical Genetics and Genomics (ACMG) guidelines.
A novel pathogenic homozygous frameshift variant, NM_001042472.3:c.601dup, p.(Val201GlyfsTer4), was identified in exon 6 of ABHD12 (ACMG criteria: PVS1 and PM2, PM1, PM4, PP3, and PP4). Through Sanger sequencing, we showed that this variant is co-segregated with the disease in the family. Further medical evaluations confirmed the compatibility of the patients’ phenotype with PHARC syndrome.
Our findings expand the spectrum of mutations in the ABHD12 and emphasize the significance of multidisciplinary diagnostic collaboration among clinicians and geneticists to solve the differential diagnosis of related disorders. Moreover, a summary based on mutations found so far in the ABHD12 gene did not suggest a clear genotype-phenotype correlation for PHARC syndrome.
Concurrent impairments of the essential senses of hearing and vision greatly influence affected individuals’ quality of life and often result in morbidity and mortality [1,2,3,4]. This accompaniment accounts for nearly 0.015% of the general population, with patients under 18 years of age making up 5.7% of this group . Among diverse etiological reasons for these impairments, heritable factors are estimated to be responsible for 27% of cases . Usher syndrome has the highest frequency among such impairments [5, 6]; other syndromes include PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract) syndrome (OMIM: 612674), Heimler syndrome 1 (OMIM: 234580), Alstrom syndrome (OMIM: 203800), Bardet-Biedel syndrome (OMIM: 209900), and Cone-rod dystrophy and hearing loss 1 (OMIM: 617236).
PHARC syndrome is an autosomal recessive neurodegenerative disease influencing the peripheral and central nervous systems. Its name is taken from its significant features, including polyneuropathy, hearing loss, ataxia, retinitis pigmentosa (RP), and cataract , although not all of these features necessarily manifest at the initial presentation [7, 8]. Some patients show only some of these symptoms for years so affected individuals are usually misdiagnosed with other neurodegenerative diseases like Usher syndrome, RP, Refsum, Charcot-Marie-Tooth, and mitochondrial diseases [8, 9]. Genetic testing can lead to a definitive diagnosis by differentiating between these similar syndromes.
Loss of function mutations in the ABDH12 gene (OMIM: 613599) cause PHARC syndrome. This gene contains 13 coding exons on chromosome 20 and translates to an α/βhydrolase domain-containing 12 (ABHD12) protein. The ABHD12 protein is a kind of enzyme that participates in lipid metabolism by catalyzing 2-arachidonoyl glycerol (2-AG) . 2-AG, as the main endocannabinoid lipid transmitter, acts in neuroinflammation and synaptic plasticity. The endocannabinoid system participates in different biological processes, for instance, neurotransmission, inflammation, mood, appetite, pain appreciation, and addiction behavior . ABHD12 is expressed in different mouse tissues, but the highest expression has been observed in microglia and macrophages, especially in the brain . Since a single functional copy of ABHD12 makes sufficient enzyme activity therefore, heterozygous carriers do not present any clinical features [11, 12].
The current challenge of diagnosing PHARC syndrome makes it essential to investigate its clinical and genetic features. Increasing data in these areas can expand the current knowledge about its onset, the existence of genotype-phenotype correlations, and the natural history of PHARC syndrome; it may also help introduce new potential treatment strategies.
This report presents the clinical manifestation of two affected individuals from a consanguineous Iranian family with mild sensory symptoms, progressive hearing impairment, cataract, and RP. Whole-exome sequencing (WES), followed by segregation analysis, confirmed a novel biallelic mutation in ABHD12. We also compared the clinical presentation and molecular findings of these patients with the previous reports of PHARC syndrome to gain a better realization of the genotype-phenotype correlations of ABHD12.
Study participants and clinical evaluations
In this study, two Iranian consanguineous siblings with mild sensory symptoms, progressive hearing impairment, RP, and cataract were enlisted (Fig. 1a). The proband (IV.1) was a 25-year-old male; his 18-year-old sister (IV.2) had the same manifestation but with milder symptoms. Clinical examinations, involving family history and physical exams, were conducted in Hazrat Rasoul Akram Hospital, Tehran, Iran. The patients (IV.1 and IV.2) were examined by otologists, ophthalmologists, and neurologists.
Standard conventional audiometry, including air- and bone-conduction testing, was carried out for IV.1, IV.2, III.1, and III.2 . Additionally, a complete ophthalmologic examination of the afflicted individuals (IV.1 and IV.2) included assessments of best-corrected visual acuity (BCVA), slit lamp bio microscopy, electroretinography (ERG), and optic coherence tomography (OCT). Neurological evaluations include electromyographic recordings, nerve conduction studies comprising measurements of motor and sensory nerves of the upper and lower extremities, and magnetic resonance brain imaging (MRI). Routine laboratory testing was conducted, including tests for liver transaminases, glomerular filtration rate, complete blood count, and electrolytes. Genomic DNA was extracted from blood samples (5 mL) of patients and healthy parents as described before .
Whole-exome sequencing and bioinformatics analysis
WES was done based on the previous works [15, 16]. Briefly, the exomes were captured by the SureSelect Human All Exon V7 Kit (Agilent, Santa Clara, CA, USA). Sequencing was done on an Illumina Hiseq2000 system (Illumina, San Diego, USA) with a mean coverage of 100X. The GRCh38/hg38 genome assembly was used to align reads.
To reach the disease-causing variants, firstly, the variants with minor allele frequency above 1% in databases like bSNP , gnomAD , and Iranome  were removed from the WES data of the patient. Secondly, synonymous changes and all non-coding areas other than the 20 bp flanking regions were eliminated. Bioinformatics techniques such as SIFT , Polyphen2 , MutationTaster , PROVEAN , and Combined Annotation Dependent Depletion  were used to predict the outcomes of the variants. According to patients’ clinical manifestations (e.g., sensorimotor neuropathy, hearing impairment, and abnormal eye physiology), the remaining variations were prioritized using ClinVar , Human Gene Mutation Database (HGMD) , human phenotype ontology , and Deafness Variation Database (DVD) . Variant interpretation followed the ACMG/AMP (American College of Genetics and Genomics/Association for Molecular Pathology) recommendations .
Family segregation study and protein analysis
Direct Sanger sequencing was used to verify the identified variants in affected members, and co-segregation analysis of the causative homozygous variant was done on all family members. The primers for the area of interest were designed using Primer3 software . The forward primer: 5′-GTCTTTGTCAGGACCCAGGA-3′ and the reverse primer: 5′-AGTCAGGCAGCATGTCACAG-3′ were used to amplify the identified variant in ABHD12. PCR was done in standard conditions . The PCR products were used for direct Sanger sequencing and the data were analyzed using Codon code aligner V.5.1.5.
To study the effect of identified mutation on the ABHD12 functional domains ConSurf server (https://consurf.tau.ac.il/) and UniProt  were used. Swiss-Model software (https://swissmodel.expasy.org/interactive) was used to design the 3D structure of the protein. I-Mutant3.0 was used to predict protein stability (http://gpcr2.biocomp.unibo.it/cgi/predictors/I-Mutant3.0/I-Mutant3.0.cgi), and MetaDome  was used to recognize the intolerant areas in the ABHD12 protein.
In November 2022, a thorough search was conducted in Google Scholar and PubMed using the terms ABHD12 and PHARC syndrome. All original English full-text articles and case reports with clinical and genetic information were added. Available phenotype and genotype were included.
The patients were born to a first-cousin marriage (Fig. 1a). Both patients presented bilateral pes cavus. Audiology evaluations showed a progressive sensorineural hearing impairment in patients (IV.1 and IV.2) that was first distinguished at the age of 11. The audio profiles of patients at different ages are shown in (Fig. 1d, e), and air conduction audiograms of their healthy parents are presented in (Fig. 1b,c).
A physical examination of IV.1 indicated mild symptoms of stance ataxia with positive Romberg and tandem gait signs, while IV.2 was normal. Heel-to-shin and finger-to-nose tests were normal in both patients, and sensory deficits in the sensation of temperature, vibration, and touch could not be found. Furthermore, both patients’ tendon reflexes in the upper and lower extremities were normal, and muscular atrophy and weakness were absent. Routine laboratory tests were normal in both patients.
Both patients’ nerve conduction studies revealed a chronic demyelinating sensorimotor neuropathy with uniform conduction, showing that nerve conduction velocities were well below 40 m/s in both the upper and lower extremities.
Electromyographic recordings in both patients displayed a regular pattern of the motor unit. Pathologic spontaneous activity could not be found.
Ophthalmologic examination and brain imaging
An ophthalmologic examination revealed that BCVA was 2/10 and 2/10 for IV.1 and 9/10 and 8/10 for IV.2 for the right and left eyes, respectively. Patient IV.1 showed a bilateral moderate posterior subcapsular cataract, while his younger sister (IV.2) showed a bilateral mild posterior subcapsular cataract. Both patients showed signs of RP in fundus autofluorescence (FAF), OCT, and ERG (Fig. 2and Fig. 3). The MRI of the brain of patient IV.1 revealed cerebellar atrophy (Fig. 4), while it was normal in patient IV.2.
Four family members were evaluated in total (Fig. 1a). Firstly, based on the ACMG guidelines for screening for genes associated with hearing loss , the absence of mutation in GJB2 was investigated in both patients (IV.1 and IV.2) [32, 33]. After the analysis of the exome sequencing data on IV.1 (Fig. 5b), a novel frameshift duplication in exon six of the ABHD12 gene—NM_001042472.3: c.601 dup; p.(Val201GlyfsTer4)— that co-segregated with the phenotype was identified (Figs. 1a and 5a). The variant was not reported in ClinVar, DVD, HGMD, dbSNP v.154, and gnomAD. The allele frequency for this variant was zero in Iranome (local database).
This variant is located in the αβ-hydrolase domain of the ABHD12 protein (Fig. 6a). We further confirmed this finding by using I-Mutant3.0, which exhibited that this variant can bring the protein close to an unstable (Free Energy change value < − 3.03) and predict its effect on human health (Disease RI: 5). Actually, the I-mutant server calculates the free energy of mutant protein and negative value of free energy change shows a decrease in protein stability. The MetaDome (a server for analysis the mutation tolerance at each position in a human protein) results indicated that this variant was situated in the intolerant regions of the ABHD12 protein (Fig. 6b).
We classified the novel frameshift based on ACMG/AMP guidelines (Criteria: PVS1 and PM2, PM1, PM4, PP3, and PP4) as “pathogenic” variant .
A comprehensive analysis of ABHD12 variants was carried out. Data from this research were compared with 14 previously published articles [7,8,9, 11, 12, 34,35,36,37,38,39,40,41,42]. In summary, 58 patients from 38 families were included. 29 distinct ABHD12 mutations have been identified in these published articles. Their phenotype, genotype, age, and sex are summarized in (Table 1), while all variants are illustrated in Fig. 6. It has been documented that ABHD12 exhibits a broad range of clinical heterogeneity in terms of age of onset, spectrum of phenotypes, severity, and progression. Cataract and hearing impairment were the most common conditions reported in ABHD12 patients.
Most mutations reported in ABHD12 were frameshift mutations (Table 1). The c.337-338delGAinsTTT is the most common variant. only seven of these variants (c.193 C > T, c.316 + 2T > A, c.337-338delGAinsTTT, c.784 C > T, c.846-852dupTAAGAGC, c.1054 C > T, and c.1063 C > T) have been reported in more than one family.
In this study, we detected a novel frameshift variant in the ABHD12 gene in two affected Iranian siblings with PHARC syndrome from a first-cousin marriage (Fig. 1a). The identified variant, c.601dup; p.(Val201GlyfsTer4), leads to a premature stop codon (Fig. 5c), which can result in a loss of function, and was determined as a pathogenic variant in agreement with ACMG guidelines .
PHARC syndrome is distinguished by hearing impairment, polyneuropathy, RP, ataxia, and early-onset cataract. The variety of clinical symptoms showed that ABHD12 play crucial roles in the in the central and peripheral nervous systems, as well as the eye, which is confirmed by its expression patterns . ABHD12 is expressed ubiquitously and is extremely expressed in the brain, especially in microglia, macrophages, and in the retina [7, 43].
ABHD12 was detected on chromosome 20 (20p11.21) for the first time in 2010. 29 mutations in 58 patients (38 families) from 14 previously published articles related to the PHARC syndrome around the world have been introduced (Table 1; Fig. 6a). These patients exhibited clinical variability concerning the spectrum of phenotypes, disease onset, severity, and progression [7, 8], and this variability was observed both within the same family and between patients with the same variant from different families (Table 1) [8, 37]. In addition, there is no correlation between the location and type of mutation and the severity of phenotypes in patients. For example, in a comparison between two nonsense mutations (p.Arg352* and p.Arg65*), the patients with the first mutation in early adulthood showed complete phenotypes of PHARC syndrome, while the patients with the second mutation did not experience neuropathy until the fifth decade of their lives (Table 1) . The current evidence does not indicate any genotype-phenotype correlation in patients with mutations in the ABHD12 gene. However, the limited number of reported cases, the multisystemic nature of the PHARC syndrome (which leads to misdiagnosis or delayed diagnosis), delayed referral for evaluation of related phenotypes, or failure to record all phenotypes at the same time in different studies can be effective.
This study’s proband (IV.1) manifested a typical PHARC phenotype, the onset of which dates to the patient’s early teenage years. It had a progressive nature, eventually revealing hearing impairment, bilateral posterior subcapsular cataract, ataxia, demyelinating polyneuropathy, and RP. The clinical picture was completely compatible with PHARC syndrome when the patient was 24 years old. The progression of the disease in the second affected family member was the same, though the symptoms were milder.
In line with most previous studies, sensorineural hearing impairment was the first manifestation in both patients (Table 1). Figure 1 indicates the progress of hearing impairment in both patients. Both patients developed posterior subcapsular cataract during childhood, corroborating previous reports showing that posterior subcapsular cataract frequently occurs in RP patients at a young age . Similar to previous studies, our patients’ definitive diagnosis of PHARC syndrome after a long follow-up period was possible only using WES [7, 8, 35]. The multisystemic nature and slow progression of PHARC syndrome is the main reason for its misdiagnosis. Performing genetic testing next to clinical findings could lead to early diagnosis, timely referrals, and better management of future symptoms.
The ABHD12 gene encodes a 398-amino acid protein product that participates in endocannabinoid metabolism and synaptic plasticity. This product is called the ABHD12 protein, which is a member of the serine hydrolase family and inactivates the endocannabinoid neurotransmitter 2-AG [35, 38]. Furthermore, previous in vivo studies indicated the lysophosphatidylserine (LPS) lipase activity of Abhd12 in the mouse brain and the accumulation of LPS in the mouse model. This accumulation increases phagocytosis activity and microglial activation, which causes neuroinflammation and atrophy in the cerebellum. This neuroinflammation is the presumed cause of motor and auditory defects over time [45,46,47].
ABHD12 is a single-pass integral membrane protein with a transmembrane helix in the N-terminal region and an extracellular active site domain in the C-terminal region . The αβ-hydrolase domain of ABHD12 consists of a lipase motif and catalytic triad (predicted amino acid residues S246-D333-H372), which serves as a fully conserved structure in both humans and rodents . This domain expands between residues 165–351 of ABHD12 (Fig. 6) . The p.(Val201GlyfsTer4) variant occurs within the conserved αβ-hydrolase domain and causes a premature stop codon, which may result in nonsense-mediated decay and, consequently, a lack of the protein product. Navia-Paldanius et al. have shown that site-directed mutagenesis of residues of the catalytic triad of the αβ-hydrolase domain abolished the enzymatic activity of ABHD12 . The research group of Tingaud-Sequeira et al. with functional studies on p.R352* mutation that produces a truncated protein have proved the loss of enzyme activity . Moreover, the variants in this domain are likely to disturb interactions with other molecules or other parts of the protein and affect protein function .
However, further research is required to fully understand the cellular, molecular, and biochemical mechanisms through which ABHD12 contributes to the PHARC syndrome. Such research could lead to earlier diagnosis, appropriate referrals, effective prognosis for future rehabilitations, improved medical management of disease progression, better genetic counseling, and prevention strategies, and a higher increasing quality of life for patients and their relatives.
A significant limitation in this research pertains to the inability to perform a functional analysis that would elucidate the specific contribution of the newly identified variant to PHARC syndrome.
We elucidated the role of a novel pathogenic mutation in the ABHD12 as a genetic reason of PHARC syndrome in an Iranian family. Additionally, we demonstrated the value of using WES for the early diagnosis of this syndrome. Our findings extend the mutation spectrum of ABHD12 by introducing a novel mutation. We also summarized previously reported mutations in the ABHD12 gene throughout the world and compared them to the new mutation investigated in the present study. We believe these results can help practitioners identify disease pathology and manage the phenotypes in a multidisciplinary setting.
The datasets produced during this manuscript are available from the corresponding author upon reasonable request. The novel variant and phenotypes were submitted in ClinVar database (accession number: VCV001727244.1) and available at (https://www.ncbi.nlm.nih.gov/clinvar/variation/1727244/).
polyneuropathy hearing loss ataxia retinitis pigmentosa cataracts
α/βhydrolase domain-containing 12
best-corrected visual acuity
optic coherence tomography
magnetic resonance brain imaging
American College of Medical Genetics/Association for Molecular Pathology
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We are so grateful to the family members for their collaboration in this study.
This work was supported by Iran University of Medical Sciences, Tehran, Iran (Grant Number: 1400-2-22-21218). The funding bodies played no role in the study design, data collection and analysis, decision to publish and writing of the manuscript.
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The study was conducted in accordance to the guidelines of the Declaration of Helsinki, and approved by the ethics committee of Iran University of Medical Sciences (Tehran, Iran). (Approval number: IR.IUMS.REC.1400.862). Informed consent was obtained from all subjects and/or their legal guardian(s).
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Daneshi, A., Garshasbi, M., Farhadi, M. et al. Genetic insights into PHARC syndrome: identification of a novel frameshift mutation in ABHD12. BMC Med Genomics 16, 235 (2023). https://doi.org/10.1186/s12920-023-01682-w