Mosaic paternal genome‐wide uniparental isodisomy with down syndrome

Darcy, Diana; Atwal, Paldeep S.; Angell, Cathy; Gadi, Inder K.; Wallerstein, Robert

doi:10.1002/ajmg.a.37187

Cited by 17 publications

(18 citation statements)

References 34 publications

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“…In our experience, the rare nature of INAD make it a challenging diagnosis, and families are often on a diagnostic odyssey despite parental and medical awareness the child is not developing normally. This delay between symptom onset and diagnosis is in line with other pediatric genetic diseases (2,11,(13)(14)(15)(16)(17)(18)(19).…”

Section: Resultssupporting

confidence: 75%

The Infantile Neuroaxonal Dystrophy Rating Scale (INAD-RS)

Atwal

Midei

Adams

et al. 2020

Preprint

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Background: INAD is an autosomal recessive neurogenetic disorder caused by biallelic pathogenic variants in PLA2G6. The downstream enzyme, iPLA2, plays a critical role in cell membrane homeostasis by helping to regulate levels of phospholipids. The clinical presentation occurs between 6 months and 3 years with global developmental regression, hypotonia, and progressive spastic tetraparesis. Progression is often rapid, resulting in severe spasticity, visual impairment, and cognitive decline, with many children not surviving past the first decade of life. To date, no accepted tool for assessing the severity of INAD exists; other commonly used scales (e.g. CHOP-INTEND, Modified Ashworth, Hammersmith Functional Motor Scale) do not accurately gauge the current severity of INAD, nor are they sensitive/specific enough to monitor disease progression. Finally, these other scales are not appropriate, because they do not address the combination of CNS, peripheral nerve, and visual pathology that occurs in children with INADMethods: We have developed and validated a structured neurological examination for INAD (scored out of 80). The examination includes six main categories of pediatric developmental evaluation: 1) gross motor-and-truncal-stability skills, 2) fine motor skills, 3) bulbar function, 4) ocular function, 5) temporo-frontal function, and, 6) Functional evaluation of the autonomic nervous system. A cohort of patients diagnosed with INAD were followed prospectively to validate the score against disease severity and disease progression. Results: We show significant correlation between the total neurological assessment score and months since symptom onset with a statistically significant (p = 6.7 x 10-07) correlation between assessment score and disease onset. As hypothesized, the coefficient of months-since-symptom-onset is strongly negative, indicating a negative correlation between total score and months since symptom onset.Conclusion: We have developed and validated a novel neurological assessment score in INAD that demonstrates strong correlation with disease severity and disease progression.

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Section: Resultssupporting

confidence: 75%

The Infantile Neuroaxonal Dystrophy Rating Scale (INAD-RS)

Atwal

Midei

Adams

et al. 2020

Preprint

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“…The presented patient is the oldest reported individual with an MGWpatUPD; the other patients range in age from 1 month to 30 years (Table ) . Obviously, all patients are female, as an androgenetic lineage (containing two Y chromosomes and no X chromosome) is not viable.…”

Section: Discussionmentioning

confidence: 92%

“…In 1995, mosaic genome‐wide paternal UPD (MGWpatUPD) was first described in a patient with BWS and a Wilms tumor . Since then, 17 additional cases have been described (Table ) …”

Section: Introductionmentioning

confidence: 99%

Multiple tumors due to mosaic genome‐wide paternal uniparental disomy

Postema

Bliek

Noesel

et al. 2019

Pediatric Blood & Cancer

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Mosaic genome‐wide paternal uniparental disomy is an infrequently described disorder in which affected individuals have signs and symptoms that may resemble Beckwith–Wiedemann syndrome. In addition, they can develop multiple benign and malignant tumors throughout life. Routine molecular diagnostics may not detect the (characteristic) low level of mosaicism, and the diagnosis is likely to be missed. Genetic counseling and a life‐long alertness for the development of tumors is indicated. We describe the long diagnostic process of a patient who already had a tumor at birth and developed multiple tumors in childhood and adulthood. Furthermore, we offer clues to recognize the entity.

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“…Interestingly, some cases with mosaic genome-wide parental UPD contain a mosaicism for a further unbalanced chromosome disorder [ 18 , 22 , 29 ]. This may indicate that cases are missed and interpreted as normal when no second cell line with aberrant copy number of chromosomes is involved.…”

Section: Discussionmentioning

confidence: 99%

Mosaic genome-wide maternal isodiploidy: an extreme form of imprinting disorder presenting as prenatal diagnostic challenge

et al. 2017

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BackgroundUniparental disomy of certain chromosomes are associated with a group of well-known genetic syndromes referred to as imprinting disorders. However, the extreme form of uniparental disomy affecting the whole genome is usually not compatible with life, with the exception of very rare cases of patients with mosaic genome-wide uniparental disomy reported in the literature.ResultsWe here report on a fetus with intrauterine growth retardation and malformations observed on prenatal ultrasound leading to invasive prenatal testing. By cytogenetic (conventional karyotyping), molecular cytogenetic (QF-PCR, FISH, array), and methylation (MS-MLPA) analyses of amniotic fluid, we detected mosaicism for one cell line with genome-wide maternal uniparental disomy and a second diploid cell line of biparental inheritance with trisomy X due to paternal isodisomy X. As expected for this constellation, we observed DNA methylation changes at all imprinted loci investigated.ConclusionsThis report adds new information on phenotypic outcome of mosaic genome-wide maternal uniparental disomy leading to an extreme form of multilocus imprinting disturbance. Moreover, the findings highlight the technical challenges of detecting these rare chromosome disorders prenatally.Electronic supplementary materialThe online version of this article (10.1186/s13148-017-0410-y) contains supplementary material, which is available to authorized users.

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Mosaic paternal genome‐wide uniparental isodisomy with down syndrome

Cited by 17 publications

References 34 publications

The Infantile Neuroaxonal Dystrophy Rating Scale (INAD-RS)

The Infantile Neuroaxonal Dystrophy Rating Scale (INAD-RS)

Multiple tumors due to mosaic genome‐wide paternal uniparental disomy

Mosaic genome-wide maternal isodiploidy: an extreme form of imprinting disorder presenting as prenatal diagnostic challenge

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