A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants

Defects in USH2A cause both isolated retinal disease and Usher syndrome (ie, retinal disease and deafness). To gain insights into isolated/nonsyndromic USH2A retinopathy, we screened USH2A in 186 probands with recessive retinal disease and no hearing complaint in childhood (discovery cohort) and in 84 probands with recessive retinal disease (replication cohort). Detailed phenotyping, including retinal imaging and audiological assessment, was performed in individuals with two likely disease-causing USH2A variants. Further genetic testing, including screening for a deep-intronic disease-causing variant and large deletions/duplications, was performed in those with one likely disease-causing change. Overall, 23 of 186 probands (discovery cohort) were found to harbour two likely disease-causing variants in USH2A. Some of these variants were predominantly associated with nonsyndromic retinal degeneration (‘retinal disease-specific''); these included the common c.2276 G>T, p.(Cys759Phe) mutation and five additional variants: c.2802 T>G, p.(Cys934Trp); c.10073 G>A, p.(Cys3358Tyr); c.11156 G>A, p.(Arg3719His); c.12295-3 T>A; and c.12575 G>A, p.(Arg4192His). An allelic hierarchy was observed in the discovery cohort and confirmed in the replication cohort. In nonsyndromic USH2A disease, retinopathy was consistent with retinitis pigmentosa and the audiological phenotype was variable. USH2A retinopathy is a common cause of nonsyndromic recessive retinal degeneration and has a different mutational spectrum to that observed in Usher syndrome. The following model is proposed: the presence of at least one ‘retinal disease-specific'' USH2A allele in a patient with USH2A-related disease results in the preservation of normal hearing. Careful genotype–phenotype studies such as this will become increasingly important, especially now that high-throughput sequencing is widely used in the clinical setting.     

Autosomal recessive Leber's hereditary optic neuropathy caused by a homozygous variant in DNAJC30 gene

Recently, Stenton et al. (2021) described a new, autosomal recessive inheritance pattern of Leber's hereditary optic neuropathy (LHON) caused by missense variants in the DNAJC30 gene. The DNAJC30 c.152A > G, p.(Tyr51Cys) variant was by far the most common variant reported in patients originating from Eastern Europe, therefore, it is believed to be a founder variant in these populations. We report the first two cases of DNAJC30-linked autosomal recessive LHON in a young male and a female originating from Estonia. The patients presented severe loss of central vision and clinical features indistinguishable from mitochondrial LHON. The whole exome sequencing carried out in the male patient and the next-generation sequencing panel in the young female patient identified the same homozygous missense variant in the DNAJC30 gene. Our cases further reinforce the pathogenicity of c.152A > G, p.(Tyr51Cys) DNAJC30 variant causing autosomal recessive LHON. According to the gnomAD database, the allele frequency of this variant in the Estonian population is 0.8%, translating into a prevalence of carriers of 1:60. It is the highest among different gnomAD populations. Applying the Hardy-Weinberg equation, an estimated 92 persons in the Estonian population carry the homozygous variant c.152A > G, p.(Tyr51Cys) in DNAJC30. In patients with LHON, we advise sequencing both the DNAJC30 gene and mitochondrial DNA simultaneously.     

Severe coarctation of the aorta,developmental delay,and multiple dysmorphic features in a child with SMAD6 and SMARCA4 variants

Pathogenic variants in SMARCA4 cause Coffin-Siris syndrome (CSS) while those in SMAD6 lead to aortic valve disease and other dysmorphisms. We identified a 6-year-old Thai boy with features of CSS alongside unusual manifestations including, very severe coarctation of the aorta (CoA) requiring coarctectomy in the neonatal period and bilateral radioulnar synostoses. Trio exome sequencing revealed that the patient harbored two de novo variants, a missense c.2475G > T, p.(Trp825Cys) in SMARCA4 and a nonsense c.652C > T, p.(Gln218Ter) in SMAD6. Both of which have never been previously reported. The clinical presentations in our patient are a result of the combinational features of each genetic variant: the SMARCA4 p.(Trp825Cys) variant leads to facial features of Coffin Siris syndrome and Dandy-Walker malformation, while the SMAD6 p.(Gln218Ter) variant underlies radioulnar synostosis. Interestingly, the severity of CoA in the proband is beyond the phenotypic spectra of each genetic variant and may be a result of the synergistic effects of both variants. Here, we report a child with variants in SMARCA4 or SMAD6 with combined features of each plus a severe CoA, possibly due to an additive effect of each variant.     

A novel homozygous missense variant in MATN3 causes spondylo-epimetaphyseal dysplasia Matrilin 3 type in a consanguineous family

Spondylo-epimetaphyseal dysplasia Matrilin 3 type (SEMD) is a rare autosomal recessive skeletal dysplasia characterized by short stature, abnormalities in the vertebral bodies and long bones, especially the lower limbs. We enrolled a consanguineous family from Pakistan in which multiple siblings suffered from severe skeletal dysplasia. The six affected subjects ranged in heights from 100 to 136 cm (~-6 standard deviation). Lower limb abnormalities with variable varus and valgus deformities and joint dysplasia were predominant features of the clinical presentation. Whole exome sequencing (WES) followed by Sanger sequencing identified a missense variant, c.542G > A, p.(Arg181Gln) in MATN3 as the genetic cause of the disorder. The variant was homozygous in all affected individuals while the obligate carriers had normal heights with no skeletal symptoms, consistent with a recessive pattern of inheritance. Multiple sequence alignment revealed that MATN3 domain affected by the variant is highly conserved in orthologous proteins. The c.542G > A, p.(Arg181Gln) variant is only the fourth variant in MATN3 causing an autosomal recessive disorder and thus expands the genotypic spectrum.     

Biallelic variants in four genes underlying recessive osteogenesis imperfecta

Osteogenesis imperfecta (OI) is an inherited heterogeneous rare skeletal disorder characterized by increased bone fragility and low bone mass. The disorder mostly segregates in an autosomal dominant manner. However, several rare autosomal recessive and X-linked forms, caused by mutations in 18 different genes, have also been described in the literature.Here, we present five consanguineous families segregating OI in an autosomal recessive pattern. Affected individuals in the five families presented severe forms of skeletal deformities. It included frequent bone fractures with abnormal healing, short stature, facial dysmorphism, osteopenia, joint laxity, and severe scoliosis. In order to search for the causative variants, DNA of at least one affected individual in three families (A-C) were subjected to whole exome sequencing (WES). In two other families (D-E), linkage analysis using highly polymorphic microsatellite markers was followed by Sanger sequencing. Sequence analysis revealed two novels and three previously reported disease-causing variants. The two novel homozygous variants including [c.824G > A; p.(Cys275Tyr)] in the SP7 gene and [c.397C > T, p.(Gln133*)] in the SERPINF1 gene were identified in families A and B, respectively. The three previously reported homozygous variants including [c.497G > A; p.(Arg166His)] in the SPARC gene, (c.359-3C > G; intron 2) and [c.677C > T; p.(Ser226Leu)] in the WNT1 gene were identified in family C, D, and E.In conclusion, our findings provided additional evidence of involvement of homozygous sequence variants in the SP7, SERPINF1, SPARC and WNT1 genes causing severe OI. It also highlights the importance of extensive genetic investigations to search for the culprit gene in each case of skeletal deformity.     

Identification and functional analysis of CORIN variants in hypertensive patients

Corin is a serine protease that activates atrial natriuretic peptide (ANP). CORIN gene variants have been reported in patients with hypertension. To date, however, the prevalence of CORIN variants in hypertensive patients remains unknown. To understand the prevalence and functional significance of CORIN variants in hypertension, we sequenced CORIN exons in 300 normal and 401 hypertensive individuals in a Chinese population and identified nine nonsynonymous variants, of which eight were not characterized previously. Among them, variants c.131A > G (p.Tyr13Cys), c.376G > T (p.Asp95Tyr), c.1094T > G (p.Leu334Trp), and c.1667G > A (p.Arg525His) occurred similarly in both normal and hypertensive individuals. Variants c1139G > A (p.Arg349His), c.2689C > T (p.Pro866Ser), and c.2864C > T (p.Thr924Met) were found once each in hypertensive individuals. Variant c.1683G > T (p.Arg530Ser) occurred preferentially in hypertensive individuals [10/401 (2.5%) vs. 1/300 (0.3%) in normal individuals; P = 0.023], which was confirmed in another independent cohort [9/368 (2.44%) in hypertensive and 2/377 (0.53%) in normal individuals; P = 0.033]. In biochemical and cell‐based functional studies, variants p.Arg530Ser and p.Thr924Met, but not p.Tyr13Cys, p.Asp95Tyr, p.Leu334Trp, p.Arg349His, p.Arg525His, and p.Pro866Ser, exhibited reduced pro‐ANP processing activity, which was caused by endoplasmic reticulum retention and poor zymogen activation, respectively. These results indicate that genetic variants impairing corin function are not uncommon in general populations and that such variants may be an important contributing factor in hypertension.     

The impact of exome sequencing on the diagnostic yield of muscular dystrophies in consanguineous families

Muscular dystrophies (MDs) are a heterogeneous group of inherited disorders that are characterized by progressive skeletal muscle weakness and dystrophic changes on muscle biopsy. The broad genetic and clinical heterogeneity of MDs make the accurate diagnosis difficult via conventional approaches. This study investigated 23 patients from eight unrelated consanguineous families with MDs. Previous clinical assessments did not accurately clarify the type of their MD and/or misdiagnose them with another disease. Exome sequencing (ES) is an efficient, time-saving, and cost-effective tool, enabling disease-causing variant (DCV) detection in affected individuals. We investigated the use of ES to diagnose MD and discover the underlying genetic etiology. We achieved a remarkable diagnostic success rate of 87.5% (7 out of 8 families) which is the highest rate reported thus far compared to previous studies. We identified two novel pathogenic variants in DYSF gene (c.4179delG, c.1149+3G > C). The latter variant impacts the splicing machinery of DYSF mRNA. Moreover, we further assessed the pathogenicity of four recurrent variants ((DYSF, c.4076T > C), (GMPPB, c.458C > T), (SGCA, c.739G > A) (TTN, c.7331G > A), designated their neurological impact and added new phenotypes in patients with these variants. To our knowledge, this is the first study applying an ES-based comprehensive molecular diagnosis to Jordanian cohort with MDs. Our findings confirmed that ES is a powerful approach for the diagnosis of MD patients. This efficient method of molecular diagnosis is crucial for guiding patient clinical care, genetic counseling, and most importantly, paving the way for gene therapy which is currently in clinical trials.     

Phenotypic variability in two patients with tumor necrosis factor receptor associated periodic fever syndrome emphasizes a rare manifestation: Immunoglobulin A nephropathy

Tumor necrosis factor receptor associated periodic fever syndrome (TRAPS) is caused by heterozygote mutations in TNFRSF1A, characterized by recurrent inflammatory attacks.In this report, we described two patients with different heterozygote mutations in TNFRSF1A. Patient 1, a 15-year-old male, had suffered from recurrent fever attacks accompanied by abdominal pain, eye manifestations, and myalgia with increased acute phase reactants since the age of 6-month. He had been unsuccessfully treated with colchicine for having familial Mediterranean fever without an identifiable MEFV mutation since the age of 4-year. At the age of 15 years, he was diagnosed with immunoglobulin (Ig) A nephropathy due to massive proteinuria and renal biopsy findings. Next generation sequencing revealed NM_001065.3: c.236C>T; p. (Thr79Met); T50M heterozygote mutation in TNFRFS1A. He was treated with methylprednisolone and cyclosporine for IgA nephropathy, thereafter with canakinumab for TRAPS. Patient 2, a 17-year-old female, had recurrent arthritis attacks accompanied by increased acute phase reactants for the last two months. She had neither fever attacks nor rashes or myalgia. Her physical examination was normal between attacks. Magnetic resonance imaging of both knees and ankles showed no signs of chronic arthritis. MEFV analyzes showed no mutation. Next generation sequencing revealed NM_001065.3: c.362G>A; p.(Arg121Gln); R92Q heterozygote mutation in TNFRFS1A. Arthritis attacks were treated successfully with ibuprofen thereafter.In conclusion, we wish to emphasize the diversity of the clinical manifestations between these two patients with distinct sequence variants in TNFRSF1A. Moreover, we presented a rare manifestation of TRAPS, IgA nephropathy.     

RNASEH2C c.194G>A is a Chinese-specific founder mutation in three unrelated patients with Aicardi-Goutières syndrome 3

Biallelic pathogenic variants in RNASEH2C cause Aicardi-Goutières syndrome 3 (AGS3, MIM #610329), a rare early-onset encephalopathy characterized by intermittent unexplained fever, chilblains, irritability, progressive microcephaly, dystonia, spasticity, severe psychomotor retardation and abnormal brain imaging. Currently, approximately 50 individuals with AGS3 and 19 variants in RNASEH2C have been revealed. Here, we reported the novel clinical manifestations and genotypic information of three unrelated Chinese patients with AGS3 caused by pathogenic variants in RNASEH2C. In addition to three novel missense variants (c.101G>A, p.Cys34Tyr; c.401T>A, p.Leu134Gln and c.434G>T, p.Arg145Leu), one missense variant (c.194G>A, p.Gly65Asp) reoccurred in all patients but was completely absent in South Asian and other ethnicities. Our study expanded the variant spectrum of RNASEH2C and identified RNASEH2C c.194G>A as a Chinese-specific founder mutation. The novel phenotypes, including mouth ulcers, hip dysplasia, retarded dentition and hypogonadism, observed in our patients greatly enriched the clinical characteristics of AGS3.     

Biallelic TOR1A mutations cause severe arthrogryposis: A case requiring reverse phenotyping

Heterozygous mutations in TOR1A gene are known to be responsible for DYT1 dystonia with incomplete penetrance. Autosomal recessive TOR1A disease is a very recently described syndrome characterized by severe arthrogryposis, developmental delay, strabismus and tremor. A 2 month-old boy with severe arthrogryposis and developmental delay was referred to our department for genetic counseling. Dystonic movements were observed on physical examination. Whole exome sequencing revealed a homozygous nonsense variant in exon 5 of TOR1A (c.862C > T, p.Arg288*). Our results expand the phenotypic and mutational spectrum of biallelic TOR1A disease, while emphasizing the importance of reverse phenotyping in the diagnosis of rare genetic disorders.     

Genotype‐specific progression of hereditary medullary thyroid cancer

Although already 25 years into the genomic era, age‐related progression of hereditary medullary thyroid cancer (MTC), the prevalence of which is estimated at one in 80,000 inhabitants, remains to be delineated for most unique RET (REarranged during Transfection) mutations. Included in this study were 567 RET carriers. The age‐related progression of MTC across histopathological groups (normal thyroid/C‐cell hyperplasia; node‐negative MTC; node‐positive MTC) was statistically significant for 13 unique RET mutations (p.Cys611Phe/c.1832G > T; p.Cys611Tyr; p.Cys618Ser/c.1852T > A; p.Cys620Arg; p.Cys634Arg; p.Cys634Phe; p.Cys634Ser; p.Cys634Tyr; p.Glu768Asp; p.Leu790Phe/c.2370G > T; p.Val804Met; p.Ser891Ala; p.Met918Thr), whereas two unique RET mutations (p.Cys618Phe; p.Cys634Gly) trended toward statistical significance. When grouped by mutational risk (highest; high; moderate – high; low – moderate; polymorphism), the age‐related progression of MTC was significant for all four categories of RET mutations, which differed significantly across and within the three histopathological groups. For high, for moderate–high, and for low–moderate risk RET mutations, the age‐related progression of MTC by mutated codon was broadly comparable across and within the three histopathological groups, and essentially unaffected by the amino acid substitutions examined. These data argue in favor of splitting the American Thyroid Association's moderate‐risk category into moderate–high and low–moderate risk categories, while emphasizing the need to contradistinguish the latter from rare nonpathogenic polymorphisms.     

Multiple HABP2 variants in familial papillary thyroid carcinoma: Contribution of a group of “thyroid-checked” controls

A heterozygous germline variant in the HABP2 gene c.1601G > A (p.Gly534Glu), which negatively impacts its tumor suppressive activity in vitro, has been described in 4–14% of kindreds of European-American ancestry with familial papillary thyroid carcinoma (fPTC). But it is also found in ≈4% of Europeans and European/Americans from public databases that, however, did not provide information on the thyroid function of the controls. To get unbiased results, we decided to compare HABP2 genotypes of patients with fPTC with those of “thyroid-checked” controls. A control group consisting of 136 European patients who were thyroidectomised for medullary thyroid carcinoma and devoid of any histologically detectable PTC or follicular-deriving carcinoma was built. In parallel we recruited 20 patients with fPTC from eleven independent European kindreds. The entire coding region of HABP2 was analyzed by Sanger sequencing the germline DNAs of patients. Nucleotide variants were searched for by Snap Shot analysis in the controls. Two variants, c.1601G > A (p.Gly534Glu) and c.364C > T (p.Arg122Trp), were found in 2 and 3 patients at the heterozygous level respectively (minor allele frequency (MAF): 5.0% and 7.5%, respectively). In controls, the MAF was either similar for the c.1601G > A HABP2 variant (2.94%, ns) or significantly lower for the c.364C > T variant (0.73%, p = 0.016). The Arg122 residue lies in the EGF-3 domain of HABP2 which is important for its activation but, however, superposition of the predicted 3D structures of the wild type and mutated proteins suggests that this variant is tolerated at the protein level. In conclusion, our data do not support the pathogenicity of the HABP2 c.1601G > A variant but highlight the existence of a new one that should be more extensively searched for in fPTC patients and its pathogenicity more carefully evaluated.     

Phenotypic and genotypic spectrum of Turkish patients with isovaleric acidemia

We aim to investigate the genetic basis of isovaleryl-CoA dehydrogenase (IVD) gene mutations and genotype–phenotype correlations in Turkish patients. Accordingly, bi-directional sequencing was performed to screen 26 patients with isovaleric acidemia (IVA). Nine novels (c.145delC, c.234 + 3G > C, c.506_507insT, p.Glu85Gln, p.Met147Val, p.Ala268Val, p.Ile287Met, p.Gly346Asp and p.Arg382Trp) and six previously reported (c.456 + 2T > C, p.Arg21His, p.Arg21Pro, p.Arg363Cys, p.Arg363His p.Glu379Lys) pathogenic mutations were identified. Pathogenicity of the novel mutations was supported using computational programs. No clear genotype–phenotype correlation could be determined. One of the cases with the novel c.234 + 3G > C mutation has portoseptal liver fibrosis, the clinical condition that was first reported for IVA. This study is the first comprehensive report from Turkey related to IVA genetics that provides information about the high number of disease-causing novel mutations.     

β2 Integrin Gene (ITGB2) mutation spectra in Pakistani families with leukocyte adhesion deficiency type 1 (LAD1)

Leukocyte adhesion deficiency I (LADI) is an autosomal recessive type of primary immunodeficiency characterized by occurrence of repeated bacterial infections, impaired pus formation and wound healing. Genetic variations in the β-2 integrin subunit encoding gene ITGB2 have been implicated in causing the disorder. In the present study, we have investigated twelve patients presenting LAD1 features. After collecting clinical and family history, flow cytometry was used to determine levels of CD18 in the patients. Clinical history revealed that umbilical cord separation occurred mostly after 19 days in the patients. Recurrent skin infections were found in seven patients. Eight patients had at least one elder sibling who died due to repeated infections. All patients had marked neutrophilia with only 0.77% of neutrophils expressing CD18. Total 12 patients suffering from LAD1 were Sanger sequenced for ITGB2 gene. Five variants, including a novel p.(Cys286Phe) and four previously reported [p.(Gly273Arg), p.(Asp128Tyr), p.(Cys62*), IVS7 + 1G > A] were identified in 8 cases, while no pathogenic variant was observed in remaining four cases. This study represents the first comprehensive clinical and genetic characterization of LAD1 in Pakistani population. This will facilitate diagnosis and genetic counselling of patients with immunodeficiency disorders in Pakistani population.     

Intermittent macrothrombocytopenia in a novel patient with Takenouchi-Kosaki syndrome and review of literature

Takenouchi-Kosaki syndrome (TKS) is a recently delineated syndromic form of thrombocytopenia strictly related to an hot-spot missense variant, p.Tyr64Cys, in CDC42 (Cell Division Control protein 42).Herein we report an additional patient with the p.Tyr64Cys aminoacidic substitution who showed the well-defined phenotypical TKS features and an intermittent, very mild, macrothrombocytopenia at 10.7 years of age (93,000/mL), that was only retrospectively valorized. Outside of this value the PLT count had always been higher than 100,000/mL. We also review literature data from patients carrying this recurrent variant.Our female patient presented with prenatal onset of short stature and microcephaly, camptodactyly, heart defects, typical facial gestalt, developmental delay, and not specific brain abnormalities. After several genetic investigations (karyotype, CGH-Array, targeted NGS analysis for short stature genes), by whole exome sequencing we identified the p.Tyr64Cys in CDC42, occurring de novo.The case presented here provides further evidence that macrothrombocytopenia can be intermittent and thus it might escape attention of clinicians. Without this key feature, TKS clinical presentation can overlap other syndromic forms of short stature. Immunodeficiency, autoimmunity, and malignancies were recently reported in patients with the p.Tyr64Cys substitution, making imperative an early diagnosis of Takenouchi-Kosaki syndrome to organize the most proper follow-up of these pediatric patients.The whole exome sequencing can be a solving tool in the challenge to the rare diseases.     

Higher frequency of TMEM199-CDG in the southern mediterranean area is associated with c.92G>C (p.Arg31Pro) mutation

Congenital disorders of glycosylation (CDG) are genetic multisystem diseases, characterized by defective glycoconjugate synthesis. A small number of CDG with isolated liver damage have been described, such as TMEM199-CDG, a non-encephalopathic liver disorder with Wilson disease-like phenotype. Only eight patients with TMEM199-CDG have been described including seven Europeans (originating from Greece and Italy) and one Chinese. Three patients from southern Italy (Campania) shared the same known missense mutation pathogenetic variant NM_152464.3:c. 92G > C (p.Arg31Pro), also found in a Greek patient.Here we report a new patient from southern Italy (Sicily), with a homozygous c.92G > C p.(Arg31Pro) variant in TMEM199. The patient's phenotype is characterized by mild non-progressive hepatopathy with a normal hepatic echo structure. A persistent increase in serum transaminases, total and low-density lipoprotein cholesterol and low serum ceruloplasmin and copper levels and normal urinary copper excretion were observed. Matrix-assisted laser desorption/ionization mass spectrometry analyses showed abnormal N- and O- protein glycosylation, indicative of a Golgi processing defect and supporting the function of TMEM199 in maintaining Golgi homeostasis. TMEM199-CDG is an ultra-rare CDG relatively frequent in the southern Mediterranean area (7 in 9 patients, 77%). It is mainly associated with the c.92G > C (p.Arg31Pro) pathogenetic allele globally reported in 4 out of 7 families (57%), including one from Greece and three unrelated families from southern Italy. The almost uniform clinical phenotype described in patients with TMEM199-CDG appears to reflect a higher prevalence of the same variant in patients from the southern Mediterranean area.     

EIF4ENIF1 variants in two patients with non-syndromic premature ovarian insufficiency

Premature ovarian insufficiency (POI) is a major cause of female subfertility. Although POI affects approximately 1–2% women worldwide, the etiology of a large number of POI patients remains unknown partially due to the genetic heterogeneity of POI. EIF4ENIF1 is one of the known POI-causative genes, and it plays an essential role in inhibiting mRNA translation and regulating mRNA destabilization in ovarian cells. In our study, two EIF4ENIF1 variants, c.9_11delGAG (p.R4del) (rs3834682) and c.2861G > C (p.G954A) (rs766008983) were identified in two sporadic Han Chinese POI patients through whole-exome sequencing. Both variants are rare in the human population. The two patients' mothers don't carry the rare variants and they have regular menstruation. The missense variant c.2861G > C was predicted to be deleterious by multiple bioinformatic tools. Western blot analysis further demonstrated that both of the two variants exhibited reduced mRNA and protein expression levels compared with the wild-type in vitro. Taken together, our findings reported two rare POI-associated EIF4ENIF1 variants, providing insights into genetic counseling and suggesting the contribution of EIF4ENIF1 variants in female infertility.     

c.1289G>A (p.Arg430His) variant in the epsilon isoform of the GFAP gene in a patient with adult onset Alexander disease

Alexander disease (AD) is a rare form of leukodystrophy caused by pathogenic variants in the GFAP gene. In young children the condition is fatal, while adults have variable neurological symptoms and prognosis. On magnetic resonance imaging, a pattern of atrophy of the medulla oblongata and cervical spinal cord with a ‘tadpole’ appearance is highly suggestive of adult-onset Alexander disease (AOAD). GFAP gene sequencing is used to confirm the diagnosis. Pre-mRNA of this gene undergoes alternative splicing resulting in formation of at least 8 different protein isoforms. Most patients with AD described to date have a pathogenic variant in the coding sequence of the main and the most abundant gene isoform, the GFAPα. Recently, two half-siblings with neurological symptoms and radiological signs of AOAD were reported and were not found to have any pathogenic variants in the GFAPα gene while further genetic testing by next generation sequencing revealed a c.1289G>A (p.Arg430His) variant in the alternative exon 7A of the GFAPε isoform.Here we present a case of another patient with symptoms and brain MRI pattern suggestive of AOAD. Similarly to the previously described patients, this patient did not have any pathogenic variants in the main gene isoform and had the same c.1289G>A (p.Arg430His) variant in the GFAPε. This report contributes to evidence of pathogenicity of the c.1289G>A (p.Arg430His) variant in the GFAPε.