A patient with Silver-Russell syndrome with multilocus imprinting disturbance, and Schimke immuno-osseous dysplasia unmasked by uniparental isodisomy of chromosome 2

Achromatopsia (ACHM) is a rare autosomal recessively inherited retinal disease characterized by congenital photophobia, nystagmus, low visual acuity, and absence of color vision. ACHM is genetically heterogeneous and can be caused by biallelic mutations in the genes CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, or ATF6. We undertook molecular genetic analysis in a single female patient with a clinical diagnosis of ACHM and identified the homozygous variant c.778G>C;p.(D260H) in the CNGA3 gene. While segregation analysis in the father, as expected, identified the CNGA3 variant in a heterozygous state, it could not be displayed in the mother. Microsatellite marker analysis provided evidence that the homozygosity of the CNGA3 variant is due to partial or complete paternal uniparental isodisomy (UPD) of chromosome 2 in the patient. Apart from the ACHM phenotype, the patient was clinically unsuspicious and healthy. This is one of few examples proving UPD as the underlying mechanism for the clinical manifestation of a recessive mutation in a patient with inherited retinal disease. It also highlights the importance of segregation analysis in both parents of a given patient or especially in cases of homozygous recessive mutations, as UPD has significant implications for genetic counseling with a very low recurrence risk assessment in such families.

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Uniparental isodisomy of chromosome 2 causing MRPL44-related multisystem mitochondrial disease

Molecular Biology Reports ◽

10.1007/s11033-021-06188-1 ◽

2021 ◽

Vol 48 (3) ◽

pp. 2093-2104

Author(s):

Alejandro Horga ◽

Andreea Manole ◽

Alice L. Mitchell ◽

Enrico Bugiardini ◽

Iain P. Hargreaves ◽

...

Keyword(s):

Mitochondrial Disease ◽

Chromosome 2 ◽

Uniparental Isodisomy

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Warburg Micro Syndrome 1 due to Segmental Paternal Uniparental Isodisomy of Chromosome 2 Detected by Whole-Exome Sequencing and Homozygosity Mapping

Cytogenetic and Genome Research ◽

10.1159/000509214 ◽

2020 ◽

Vol 160 (6) ◽

pp. 309-315

Author(s):

Abdullah Sezer ◽

Gülsüm Kayhan ◽

Altuğ Koç ◽

Mehmet A. Ergün ◽

Ferda E. Perçin

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Uniparental Disomy ◽

Homozygosity Mapping ◽

Spastic Diplegia ◽

Chromosome 2 ◽

Whole Exome ◽

Uniparental Isodisomy ◽

Mapping Analysis ◽

Warburg Micro Syndrome

Warburg micro syndrome (WARBM) is a rare autosomal recessive disorder characterized by microcephaly, cortical dysplasia, intellectual disability, ocular abnormalities, spastic diplegia, and microgenitalia. WARBM has 4 subtypes arising from pathogenic variants in 4 genes (RAB18, RAB3GAP1, RAB3GAP2, and TBC1D20). Here, we report on a patient with a homozygous pathogenic c.665delC (p.Pro222HisfsTer30) variant in the RAB3GAP1 gene identified by whole-exome sequencing (WES) analyses. Only his father was a heterozygous carrier, and homozygosity mapping analysis of the WES data revealed large loss-of-heterozygosity regions in both arms of chromosome 2, interpreted as uniparental isodisomy. This uniparental disomy pattern could be due to paternal meiosis I nondisjunction because of the preserved heterozygosity in the pericentromeric region. This report provides novel insights, including a rare form of UPD, usage of homozygosity mapping analysis for the evaluation of isodisomy, and the first reported case of WARBM1 as a result of uniparental isodisomy.

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Primary congenital glaucoma due to paternal uniparental isodisomy of chromosome 2 andCYP1B1deletion

Molecular Genetics & Genomic Medicine ◽

10.1002/mgg3.774 ◽

2019 ◽

Vol 7 (8) ◽

Author(s):

Emmanuelle Souzeau ◽

Andrew Dubowsky ◽

Jonathan B. Ruddle ◽

Jamie E. Craig

Keyword(s):

Congenital Glaucoma ◽

Chromosome 2 ◽

Primary Congenital Glaucoma ◽

Uniparental Isodisomy

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Maternal uniparental isodisomy of chromosome 2 leading to homozygous variants in SPR and ZNF142: case report and literature review

Molecular Genetics and Metabolism ◽

10.1016/s1096-7192(21)00239-0 ◽

2021 ◽

Vol 132 ◽

pp. S102-S103

Author(s):

Janhawi Kelkar ◽

Miriam DiMaio ◽

Deqiong Ma ◽

Hui Zhang

Keyword(s):

Case Report ◽

Literature Review ◽

Chromosome 2 ◽

Uniparental Isodisomy

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Blended Phenotype of Silver-Russell Syndrome and SPG50 Caused by Maternal Isodisomy of Chromosome 7

Neurology Genetics ◽

10.1212/nxg.0000000000000544 ◽

2020 ◽

Vol 7 (1) ◽

pp. e544

Author(s):

Marvin Ziegler ◽

Bianca E. Russell ◽

Kathrin Eberhardt ◽

Gregory Geisel ◽

Angelica D'Amore ◽

...

Keyword(s):

Short Stature ◽

Neurodevelopmental Disorder ◽

Brain Mri ◽

Adaptor Protein ◽

Chromosome 7 ◽

Imprinting Disorders ◽

Feeding Difficulties ◽

Functional Studies ◽

Uniparental Isodisomy ◽

Silver Russell Syndrome

ObjectiveUniparental isodisomy can lead to blended phenotypes of imprinting disorders and autosomal recessive diseases. To determine whether a complex neurodevelopmental disorder was caused by uniparental isodisomy, a detailed clinical and molecular characterization was performed.MethodsA combination of clinical, molecular, and imaging data and functional studies in patient-derived fibroblasts.ResultsWe report a 4-year-old female with a blended, complex phenotype of Silver-Russell syndrome (SRS) and hereditary spastic paraplegia type 50 (SPG50) caused by total maternal isodisomy of chromosome 7 (UPiD(7)mat) and a loss-of-function variant in AP4M1 (NM_00472.3: c.59-1G>C, IVS1-1G>C). Functional studies in patient-derived fibroblasts confirmed the loss of adaptor protein complex 4 function. Distinctive facial features, intrauterine growth restriction, short stature, feeding difficulties, and severe gastroesophageal reflux were consistent with SRS. Features associated with SPG50 included early-onset epilepsy, episodes of stereotypical laughter, and thinning of the corpus callosum and ventriculomegaly on brain MRI. Symptoms shared by both syndromes such as developmental delay, short stature, and axial and appendicular hypotonia were also present. Notably, other common manifestations of SPG50 such as microcephaly or spasticity had not developed yet.ConclusionsThis case highlights that atypical clinical features in patients with well-described imprinting disorders should lead to investigations for recessive conditions caused by variants in genes that localize to the region of homozygosity.

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