<i>MYT1</i> role in the microtia‐craniofacial microsomia spectrum

Luquetti, Daniela V; Heike, Carrie L.; Zarante, Ignacio; Timms, Andrew E.; Gustafson, Jonas; Pachajoa, Harry; Porras-Hurtado, Gloria Liliana; Ayala-Ramírez, Paola; Dueñas-Roque, Milagros M.; Jimenez, Natalia Arango; Ibañez, Lina María; Hurtado‐Villa, Paula

doi:10.1002/mgg3.1401

Cited by 21 publications

(17 citation statements)

References 18 publications

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“…Epibulbar dermoids also appear to be a specific clinical feature of OAVS that could compensate the absence of ear anomaly if HFM is present. Some authors recently suggested as OAVS diagnostic criteria the presence of two phenotypic findings including epibulbar dermoids such as mandibular hypoplasia and epibulbar dermoids, or preauricular tag and epibulbar dermoid or lateral oral cleft and epibulbar dermoids 25…”

Section: Clinical Diagnostic Criteriamentioning

confidence: 99%

“…Lateral oral cleft, also named macrostomia, was also proposed to be one of the two minimal clinical features by Luquetti et al , associated with either mandibular hypoplasia or preauricular tag 25…”

Section: Clinical Diagnostic Criteriamentioning

confidence: 99%

“…Overexpression of mutated forms in cellular experiments confirmed their loss-of-function effect and interestingly linked MYT1 to retinoic acid pathway, a known toxic agent in utero , leading to OAVS features on exposed newborns. Other patients with OAVS were then reported carrying MYT1 mutations, although explaining the onset of OAVS in a small percentage of patients14 25 53 (table 3).…”

Section: Aetiologiesmentioning

confidence: 99%

“…Due to high heterogeneity in this malformative spectrum, WES or WGS is recommended, in a trio manner due to sporadic occurrence of OAVS, and also in simplex, considering incomplete penetrance, in order not to discard inherited rare variants that could be of interest. Indeed, MYT1 variants are mostly inherited 25 52 64. SOLVE-RD project allows European partner centres to explore WGS in patients with OAVS whose exome is negative.…”

Section: Diagnostic Toolsmentioning

confidence: 99%

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Oculo-auriculo-vertebral spectrum: new genes and literature review on a complex disease

et al. 2022

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Oculo-auriculo-vertebral spectrum (OAVS) or Goldenhar syndrome is due to an abnormal development of first and second branchial arches derivatives during embryogenesis and is characterised by hemifacial microsomia associated with auricular, ocular and vertebral malformations. The clinical and genetic heterogeneity of this spectrum with incomplete penetrance and variable expressivity, render its molecular diagnosis difficult. Only a few recurrent CNVs and genes have been identified as causatives in this complex disorder so far. Prenatal environmental causal factors have also been hypothesised. However, most of the patients remain without aetiology. In this review, we aim at updating clinical diagnostic criteria and describing genetic and non-genetic aetiologies, animal models as well as novel diagnostic tools and surgical management, in order to help and improve clinical care and genetic counselling of these patients and their families.

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Section: Clinical Diagnostic Criteriamentioning

confidence: 99%

Section: Clinical Diagnostic Criteriamentioning

confidence: 99%

Section: Aetiologiesmentioning

confidence: 99%

Section: Diagnostic Toolsmentioning

confidence: 99%

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Oculo-auriculo-vertebral spectrum: new genes and literature review on a complex disease

et al. 2022

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“…Variants in transcription factors involved in neural crest cell migration and patterning (TFAP2A, SIX1, SIX5, EYA1, HOXA10, HOXA2), chromatin modifiers (CHD7, KMT2D, KDM6A), growth factors and their receptors (GDF6, FGF3, FGF10, FGFR2, FGFR3), DNA pre-replication complexes (ORC1, ORC4, ORC6, CDC6, CDT1), ribosome assembly (TCOF1, POL1RC, POL1RD), and the spliceosome (EFTUD2, TXNL4A, SF3B4) have been implicated in monogenic syndromes that include malformation of the ears or mandible 7 . Variants in MYT1 have been identified in unrelated individuals with CFM, suggesting a possible role in disease pathogenesis 8,9 . The two largest families described in the literature to date demonstrating dominant inheritance of CFM identified linkage of the trait to chromosomal bands 11q12-13 and 14q32; however, the responsible gene within each linkage interval was not identified at the time of study 10,11 .…”

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confidence: 99%

Haploinsufficiency of SF3B2 causes craniofacial microsomia

et al. 2021

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Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown. We perform whole-exome or genome sequencing of 146 kindreds with sporadic (n = 138) or familial (n = 8) CFM, identifying a highly significant burden of loss of function variants in SF3B2 (P = 3.8 × 10−10), a component of the U2 small nuclear ribonucleoprotein complex, in probands. We describe twenty individuals from seven kindreds harboring de novo or transmitted haploinsufficient variants in SF3B2. Probands display mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities. Targeted morpholino knockdown of SF3B2 in Xenopus results in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease. The results establish haploinsufficient variants in SF3B2 as the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases.

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Novel MYT1 variants expose the complexity of oculo‐auriculo‐vertebral spectrum genetic mechanisms

Zamariolli

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Moysés-Oliveira

et al. 2021

American J of Med Genetics Pt A

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Oculo‐auriculo‐vertebral spectrum (OAVS) is a developmental disorder characterized by anomalies mainly involving the structures derived from the first and second pharyngeal arches. The spectrum presents with heterogeneous clinical features and complex etiology with genetic factors not yet completely understood. To date, MYT1 is the most important gene unambiguously associated with the spectrum and with functional data confirmation. In this work, we aimed to identify new single nucleotide variants (SNVs) affecting MYT1 in a cohort of 73 Brazilian patients diagnosed with OAVS. In addition, we investigated copy number variations (CNVs) encompassing this gene or its cis‐regulatory elements and compared the frequency of these events in patients versus a cohort of 455 Brazilian control individuals. A new SNV, predicted as likely deleterious, was identified in five unrelated patients with OAVS. All five patients presented hearing impairment and orbital asymmetry suggesting an association with the variant. CNVs near MYT1, located in its neighboring topologically associating domain (TAD), were found to be enriched in patients when compared to controls, indicating a possible involvement of this region with OAVS pathogenicity. Our findings highlight the genetic complexity of the spectrum that seems to involve more than one variant type and inheritance patterns.

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MYT1 role in the microtia‐craniofacial microsomia spectrum

Cited by 21 publications

References 18 publications

Oculo-auriculo-vertebral spectrum: new genes and literature review on a complex disease

Oculo-auriculo-vertebral spectrum: new genes and literature review on a complex disease

Haploinsufficiency of SF3B2 causes craniofacial microsomia

Novel MYT1 variants expose the complexity of oculo‐auriculo‐vertebral spectrum genetic mechanisms

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