New ocular findings in two sisters with Yunis–Varón syndrome and literature review

Corona‐Rivera, Jorge Román; Romo‐Huerta, Carmen O.; López-Marure, Eloy; Ramos, Feliciano J.; Estrada-Padilla, Sara A.; Zepeda-Romero, Luz Consuelo

doi:10.1016/j.ejmg.2010.09.013

Cited by 11 publications

(5 citation statements)

References 14 publications

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“…1 Since then, approximately 25 individuals with Yunis-Varó n syndrome (YVS) (MIM 216340) have been described. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] Frequent features include structural brain abnormalities, sparse and pale hair, and facial dysmorphisms. Skeletal abnormalities include wide fontanelles with calvarial dysostosis, aplasia or hypoplasia of the clavicles and phalanges in the hands and feet, and absence of thumbs and halluces.…”

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“…Pictures and radiographs of most affected individuals are available in previously published case reports. 5,7,8,18,20 The study was conducted according to the guidelines of the institutional review board of the Baylor College of Medicine and informed consent was obtained prior to collection of samples. The inclusion criterion was a high index of suspicion of Yunis-Varó n syndrome by a clinical geneticist.…”

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Yunis-Varón Syndrome Is Caused by Mutations in FIG4, Encoding a Phosphoinositide Phosphatase

Campeau

Lenk

et al. 2013

The American Journal of Human Genetics

129

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Yunis-Varón syndrome (YVS) is an autosomal-recessive disorder with cleidocranial dysplasia, digital anomalies, and severe neurological involvement. Enlarged vacuoles are found in neurons, muscle, and cartilage. By whole-exome sequencing, we identified frameshift and missense mutations of FIG4 in affected individuals from three unrelated families. FIG4 encodes a phosphoinositide phosphatase required for regulation of PI(3,5)P(2) levels, and thus endosomal trafficking and autophagy. In a functional assay, both missense substitutions failed to correct the vacuolar phenotype of Fig4-null mouse fibroblasts. Homozygous Fig4-null mice exhibit features of YVS, including neurodegeneration and enlarged vacuoles in neurons. We demonstrate that Fig4-null mice also have small skeletons with reduced trabecular bone volume and cortical thickness and that cultured osteoblasts accumulate large vacuoles. Our findings demonstrate that homozygosity or compound heterozygosity for null mutations of FIG4 is responsible for YVS, the most severe known human phenotype caused by defective phosphoinositide metabolism. In contrast, in Charcot-Marie-Tooth disease type 4J (also caused by FIG4 mutations), one of the FIG4 alleles is hypomorphic and disease is limited to the peripheral nervous system. This genotype-phenotype correlation demonstrates that absence of FIG4 activity leads to central nervous system dysfunction and extensive skeletal anomalies. Our results describe a role for PI(3,5)P(2) signaling in skeletal development and maintenance.

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Yunis-Varón Syndrome Is Caused by Mutations in FIG4, Encoding a Phosphoinositide Phosphatase

Campeau

Lenk

et al. 2013

The American Journal of Human Genetics

129

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“…The presence of maculopathy in all three siblings suggests that this is part of their syndrome, but further work will be required to exclude another cause. There has been one report of a macular phenotype in Yunis‐Varon syndrome (Corona‐Rivera et al, ), suggesting that children with FIG4‐associated CNS myelination defects should undergo ocular examinations.…”

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confidence: 99%

Cerebral hypomyelination associated with biallelic variants of FIG4

et al. 2019

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The lipid phosphatase gene FIG4 is responsible for Yunis-Varón syndrome and Charcot-Marie-Tooth disease Type 4J, a peripheral neuropathy. We now describe four families with FIG4 variants and prominent abnormalities of central nervous system (CNS) white matter (leukoencephalopathy), with onset in early childhood, ranging from severe hypomyelination to mild undermyelination, in addition to peripheral neuropathy. Affected individuals inherited biallelic FIG4 variants from heterozygous parents. Cultured fibroblasts exhibit enlarged vacuoles characteristic of FIG4 dysfunction. Two unrelated families segregate the same G>A variant in the +1 position of intron 21 in the homozygous state in one family and compound heterozygous in the other. This mutation in the splice donor site of exon 21 results in read-through from exon 20 into intron 20 and truncation of the final 115 C-terminal amino acids of FIG4, with retention of partial function. The observed CNS white matter disorder in these families is consistent with the myelination defectsHuman Mutation. 2019;40:619-630. wileyonlinelibrary.com/journal/humu Yes, moderate cognitive impairment Low-borderline IQ No speech at 4 year Limited communication Limited communication Limited communication (Continues) 626 |

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“…Complete absence of both clavicles may suggest the Yunis-Varon syndrome but in this rare genetic disorder, intellectual dysfunction and anomalies of the hands and feet are associated with malformations in other systems [7] . Delayed closure of fontanels, Wormian bones, and hypoplastic clavicles are also features of pyknodysostosis, mandibuloacral dysplasia and Yunis-Varon syndrome [1] .…”

Section: Discussionmentioning

confidence: 99%