High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families

Benkirane, Mehdi; Marelli, Cécilia; Guissart, Claire; Roubertie, Agathe; Ollagnon, E.; Choumert, Ariane; Fluchère, Frédérique; Magne, Fabienne Ory; Halleb, Yosra; Renaud, Mathilde; Larrieu, Lise; Baux, David; Patat, Olivier; Bousquet, Idriss; Ravel, Jean‐Marie; Cuntz-Shadfar, Danielle; Sarret, Catherine; Ayrignac, Xavier; Rolland, Anne; Juntas-Morales, Raul; Pointaux, Morgane; Lieutard-Haag, Cathy; Laurens, Brice; Tillikete, Caroline; Bernard, Emilien; Mallaret, Martial; Tranchant, Christine; Meyer, Pierre; Damaj, Léna; Pasquier, Laurent; Acquaviva, Cécile; Chaussenot, Annabelle; Isidor, Bertrand; Nguyen, Karine; Camu, William; Eusebio, Alexandre; Carrière, Nicolas; Riquet, Audrey; Thouvenot, Éric; Gonzales, Victoria; Carme, Emilie; Attarian, Shahram; Odent, Sylvie; Castrioto, Anna; Ewenczyk, Claire; Charles, Perrine; Kremer, Laurent; Sissaoui, Samira; Bahi‐Buisson, Nadia; Kaphan, Elsa; Degardin, Adrian; Doray, Bérénice; Julia, Sophie; Remerand, Ganaëlle; Fraix, Valérie; Haidar, Lydia Abou; Lazaro, Leïla; Laugel, Vincent; Villega, Frédéric; Charlin, Cyril; Frismand, Solène; Moreira, Marinha Costa; Witjas, Tatiana; Francannet, Christine; Walther‐Louvier, Ulrike; Fradin, Mélanie; Chabrol, B.; Fluss, Joël Victor; Bieth, Éric; Castelnovo, Giovanni; Vergnet, Sylvain; Meunier, Isabelle; Verloès, Alain; Brischoux‐Boucher, Elise; Coubes, Christine; Geneviève, David; Lebouc, Nicolas; Jp, Azulay; Anheim, Mathieu; Goizet, Cyril; Rivier, François; Labauge, Pierre; Calvas, Patrick; Kœnig, M.

doi:10.1038/s41436-021-01250-6

Cited by 15 publications

(16 citation statements)

References 44 publications

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“…Second, the start loss of CSNK2B was also recorded in the gnomAD database 4 with a relative high population frequencies. Considering that the start loss variant may theoretically affect the open reading frame and leads to gene silencing ( Chen et al, 2020 ), or re-initiate translation by another “ATG” triple nucleotide and mainly affects phenotypic penetrance ( Benkirane et al, 2021 ), whether those variants are pathogenic requires further study. There were eight individuals with c.G94 mutation, and detailed phenotypes were available for four individuals.…”

Section: Discussionmentioning

confidence: 99%

Splicing Interruption by Intron Variants in CSNK2B Causes Poirier–Bienvenu Neurodevelopmental Syndrome: A Focus on Genotype–Phenotype Correlations

Zhang

Ye²,

Chen³

et al. 2022

Front. Neurosci.

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CSNK2B has recently been identified as the causative gene for Poirier–Bienvenu neurodevelopmental syndrome (POBINDS). POBINDS is a rare neurodevelopmental disorder characterized by early-onset epilepsy, developmental delay, hypotonia, and dysmorphism. Limited by the scarcity of patients, the genotype–phenotype correlations in POBINDS are still unclear. In the present study, we describe the clinical and genetic characteristics of eight individuals with POBINDS, most of whom suffered developmental delay, generalized epilepsy, and hypotonia. Minigene experiments confirmed that two intron variants (c.367+5G>A and c.367+6T>C) resulted in the skipping of exon 5, leading to a premature termination of mRNA transcription. Combining our data with the available literature, the types of POBINDS-causing variants included missense, nonsense, frameshift, and splicing, but the variant types do not reflect the clinical severity. Reduced casein kinase 2 holoenzyme activity may represent a unifying pathogenesis. We also found that individuals with missense variants in the zinc finger domain had manageable seizures (p = 0.009) and milder intellectual disability (p = 0.003) than those with missense variants in other domains of CSNK2B. This is the first study of genotype–phenotype correlations in POBINDS, drawing attention to the pathogenicity of intron variants and expanding the understanding of neurodevelopmental disorders.

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Section: Discussionmentioning

confidence: 99%

Splicing Interruption by Intron Variants in CSNK2B Causes Poirier–Bienvenu Neurodevelopmental Syndrome: A Focus on Genotype–Phenotype Correlations

Zhang

Ye²,

Chen³

et al. 2022

Front. Neurosci.

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“…For example, early-onset cases are often evaluated by ophthalmologists and initially screened for genes associated with visual impairment. Juvenile- and adult-onset cases are likely to be evaluated by different physicians depending on the specific presenting symptom ( 29 – 31 ). We suggest that PNPLA6 gene screening should also be considered in the diagnostic workout of patients with late-onset cerebellar signs, including patients presenting a CANVAS-like phenotype, when pathological expansions in the RFC1 gene are not detected.…”

Section: Discussionmentioning

confidence: 99%

Multifaceted and Age-Dependent Phenotypes Associated With Biallelic PNPLA6 Gene Variants: Eight Novel Cases and Review of the Literature

et al. 2022

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A wide spectrum of neurodegenerative diseases has been associated with pathogenic variants in the PNPLA6 (patatin-like phospholipase domain-containing protein 6) gene, including spastic paraplegia type 39, Gordon—Holmes, Boucher—Neuhauser, Oliver—Mc Farlane, and Laurence—Moon syndromes. These syndromes present variable and overlapping clinical symptoms, encompassing cerebellar ataxia, hypogonadotropic hypogonadism, chorioretinal dystrophy, spastic paraplegia, muscle wasting, peripheral neuropathy, and cognitive impairment. In the present study, we performed a wide genetic screening in 292 patients presenting with ataxia or spastic paraplegia using a probe-based customized gene panel, covering >200 genes associated with spinocerebellar diseases. We identified six novel and four recurrent PNPLA6 gene variants in eight patients (2.7%). Six patients presented an infantile or juvenile onset (age <18), and two patients had an adult onset. Cerebellar ataxia was observed in seven patients and spastic paraplegia in one patient. Progression of cerebellar symptoms was slow in all patients, who retained ambulation even after a mean disease duration of 15 years. Brain MRI showed cerebellar atrophy in 6/8 patients, more pronounced in superior and dorsal vermis lobules (I to VII). Additional clinical features included hypogonadotropic hypogonadism (5/8), growth hormone deficiency (2/8), peripheral axonal neuropathy (4/8), cognitive impairment (3/8), chorioretinal dystrophy (2/8), and bilateral vestibular areflexia with a reduced visual vestibule-ocular reflex (1/8). In accordance with previous studies, chorioretinal dystrophy was the most frequent presenting symptom in early onset patients, hypogonadotropic hypogonadism in juvenile onset cases, and cerebellar ataxia in adult patients. One patient had an initial clinical presentation compatible with Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS), but no pathological expansions in the RFC1 gene. In conclusion, patients with PNPLA6 variants present a variable age of onset spanning from infancy to adulthood, and each clinical symptom has an age-dependent manifestation thus requiring a multi-systemic diagnostic approach. The description of patients presenting very late-onset cerebellar ataxia suggests that PNPLA6 genetic screening should also be considered in the diagnostic workout of adult cerebellar ataxia.

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“…It has been hypothesized that mutations changing one or a few amino acids have only a mild effect on PEX10 protein function, while nonsense-mutations leading to a shorter or incomplete protein product have a more severe effect. 7,13 We reviewed all published cases for which a clinical phenotype and genetic data was present to scrutinize this hypothesis. Our patient carries a de novo nonsense-mutation in Exon 3 and a recurrent start codon mutation.…”

Section: Discussionmentioning

confidence: 99%

“…The latter could represent a mild mutation as a transcription start site 145 codons further downstream could be used instead. 7,13 Following this argument, most, but not all, published cases presenting with the mild phenotype carry at least one mild mutation.…”

Section: Discussionmentioning

confidence: 99%

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How to Detect Isolated PEX10-Related Cerebellar Ataxia?

et al. 2022

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A 4-year-old boy presented with subacute onset of cerebellar ataxia. Neuroimaging revealed cerebellar atrophy. Metabolic screening tests aiming to detect potentially treatable ataxias showed an increased value (fourfold upper limit of normal) for phytanic acid and elevated very-long-chain fatty acid (VLCFA) ratios (C24:0/C22:0 and C26:0/C22:0), while absolute concentrations of VLCFA were normal. Genetic analysis identified biallelic variants in PEX10. Immunohistochemistry confirmed pathogenicity in the patients' cultured fibroblasts demonstrating peroxisomal mosaicism with a general catalase import deficiency as well as conspicuous peroxisome morphology as an expression of impaired peroxisomal function. We describe for the first time an elongated peroxisome morphology in a patient with PEX10-related cerebellar ataxia.A literature search yielded 14 similar patients from nine families with PEX10-related cerebellar ataxia, most of them presenting their first symptoms between 3 and 8 years of age. In 11/14 patients, the first and main symptom was cerebellar ataxia; in three patients, it was sensorineural hearing impairment. Finally, all 14 patients developed ataxia. Polyneuropathy (9/14) and cognitive impairment (9/14) were common associated findings. In 12/13 patients brain MRI showed cerebellar atrophy. Phytanic acid was elevated in 8/12 patients, while absolute concentrations of VLCFA levels were in normal limits in several patients. VLCFA ratios (C24:0/C22:0 and/or C26:0/C22:0), though, were elevated in 11/11 cases. We suggest including measurement of phytanic acid and VLCFA ratios in metabolic screening tests in unexplained autosomal recessive ataxias with cerebellar atrophy, especially when there is an early onset and symptoms are mild.

show abstract

High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families

Cited by 15 publications

References 44 publications

Splicing Interruption by Intron Variants in CSNK2B Causes Poirier–Bienvenu Neurodevelopmental Syndrome: A Focus on Genotype–Phenotype Correlations

Splicing Interruption by Intron Variants in CSNK2B Causes Poirier–Bienvenu Neurodevelopmental Syndrome: A Focus on Genotype–Phenotype Correlations

Multifaceted and Age-Dependent Phenotypes Associated With Biallelic PNPLA6 Gene Variants: Eight Novel Cases and Review of the Literature

How to Detect Isolated PEX10-Related Cerebellar Ataxia?

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