Uniparental disomy of chromosome 1 unmasks recessive mutations of PPT1 in a boy with neuronal ceroid lipofuscinosis type 1

Travaglini, Lorena; Aiello, Chiara; Alesi, Viola; Loddo, Sara; Novelli, Antonio; Tozzi, Giulia; Bertini, Enrico; Leuzzi, Vincenzo; Brancati, Francesco

doi:10.1016/j.braindev.2016.08.010

Cited by 5 publications

(4 citation statements)

References 8 publications

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“…SNP‐array technology enables the detection of copy number variations (CNVs) and regions of homozygosity (ROH) in the genome. ROH are not per se diagnostic of specific diseases, but represent an important tool for revealing uniparental disomy (UPD), consanguinity or ancestral relatedness (Kearney, Kearney, & Conlin, 2011; Travaglini et al, 2017) and mapping recessive disease genes (Alkuraya, 2010; McQuillan et al, 2008). Massive parallel sequencing has improved the identification of single nucleotide changes, with a significant impact on the diagnostic yield for patients affected by neurodevelopmental disabilities and/or congenital anomalies (Alesi et al, 2018; Bamshad, Nickerson, & Chong, 2019; Petrikin, Willig, Smith, & Kingsmore, 2015).…”

Section: Introductionmentioning

confidence: 99%

PPP1R21‐related syndromic intellectual disability: Report of an adult patient and review

Loddo

Alesi

Radio

et al. 2020

American J of Med Genetics Pt A

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Variants in PPP1R21 were recently found to be associated with an autosomal recessive intellectual disability syndrome in 9 individuals. Our patient, the oldest among the known subjects affected by PPP1R21-related syndrome, manifested intellectual disability, short stature, congenital ataxia with cerebellar vermis hypoplasia, generalized hypertrichosis, ulcerative keratitis, muscle weakness, progressive coarse appearance, macroglossia with fissured tongue, and deep palmar and plantar creases. We provide an overview of the clinical spectrum and natural history of this newly recognized disorder, arguing the emerging notion that PPP1R21 gene mutations could result in endolysosomal functional defects. The oldest patients could display a more severe clinical outcome, due to accumulation of metabolites or damage secondary to an alteration of the autophagy pathway. Follow-up of patients with PPP1R21 mutations is recommended for improving the understanding of PPP1R21-related syndromic intellectual disability.

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Section: Introductionmentioning

confidence: 99%

PPP1R21‐related syndromic intellectual disability: Report of an adult patient and review

Loddo

Alesi

Radio

et al. 2020

American J of Med Genetics Pt A

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“…In conjunction, these data supported the occurrence of paternal UPD for chromosome 1 as the source of simultaneous homozygous mutations in ABCA4 and USH2A . Various instances of recessive diseases associated with paternally derived UPD for chromosome 1 have been demonstrated, including infantile hypophosphatasia ( ALPl gene) ( Watanabe et al, 2014 ), neuronal ceroid lipofuscinosis-1 ( PPT1 ) ( Nilda et al, 2016 ; Travaglini et al, 2017 ), and atypical Hutchinson–Gilford progeria syndrome ( ZMPSTE24 ) ( Cassini et al, 2018 ) among others ( Zeng et al, 2006 ; Miura et al, 2000 ; Manoli et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Case report: Disease phenotype associated with simultaneous biallelic mutations in ABCA4 and USH2A due to uniparental disomy of chromosome 1

et al. 2022

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Inherited retinal diseases (IRDs) represent a spectrum of clinically and genetically heterogeneous disorders. Our study describes an IRD patient carrying ABCA4 and USH2A pathogenic biallelic mutations as a result of paternal uniparental disomy (UPD) in chromosome 1. The proband is a 9-year-old girl born from non-consanguineous parents. Both parents were asymptomatic and denied family history of ocular disease. Clinical history and ophthalmologic examination of the proband were consistent with Stargardt disease. Whispered voice testing disclosed moderate hearing loss. Next-generation sequencing and Sanger sequencing identified pathogenic variants in ABCA4 (c.4926C>G and c.5044_5058del) and USH2A (c.2276G>T). All variants were present homozygously in DNA from the proband and heterozygously in DNA from the father. No variants were found in maternal DNA. Further analysis of single nucleotide polymorphisms confirmed paternal UPD of chromosome 1. This is the first known patient with confirmed UPD for two recessively mutated IRD genes. Our study expands on the genetic heterogeneity of IRDs and highlights the importance of UPD as a mechanism of autosomal recessive disease in non-consanguineous parents. Moreover, a long-term follow-up is essential for the identification of retinal features that may develop as a result of USH2A-related conditions.

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“…However, adult onset CLN4 disease is dominantly inherited in the few families described with this disease ( 1 , 3 ). There are three published reports of uniparental disomy in the NCLs, one in which a patient has complete isodisomy of chromosome 8, leading to homozygosity of a maternally-inherited deletion in CLN8 ( 19 ), and two patients for CLN1, both with paternal isodisomy of chromosome 1 ( 19 , 20 ).…”

Section: Historical Perspectivementioning

confidence: 99%

The Genetic Basis of Phenotypic Heterogeneity in the Neuronal Ceroid Lipofuscinoses

Gardner

Mole

2021

Front. Neurol.

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The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders that affect children and adults. They share some similar clinical features and the accumulation of autofluorescent storage material. Since the discovery of the first causative genes, more than 530 mutations have been identified across 13 genes in cases diagnosed with NCL. These genes encode a variety of proteins whose functions have not been fully defined; most are lysosomal enzymes, or transmembrane proteins of the lysosome or other organelles. Many mutations in these genes are associated with a typical NCL disease phenotype. However, increasing numbers of variant disease phenotypes are being described, affecting age of onset, severity or progression, and including some distinct clinical phenotypes. This data is collated by the NCL Mutation Database which allows analysis from many perspectives. This article will summarise and interpret current knowledge and understanding of their genetic basis and phenotypic heterogeneity.

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Uniparental disomy of chromosome 1 unmasks recessive mutations of PPT1 in a boy with neuronal ceroid lipofuscinosis type 1

Cited by 5 publications

References 8 publications

PPP1R21‐related syndromic intellectual disability: Report of an adult patient and review

PPP1R21‐related syndromic intellectual disability: Report of an adult patient and review

Case report: Disease phenotype associated with simultaneous biallelic mutations in ABCA4 and USH2A due to uniparental disomy of chromosome 1

The Genetic Basis of Phenotypic Heterogeneity in the Neuronal Ceroid Lipofuscinoses

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