Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.

Hemifacial microsomia (HFM) is a common congenital malformation of the craniofacial region There are 3 possible pathogenic models of HFM-vascular abnormality and hemorrhage in the craniofacial region, damage to Meckel's cartilage, and the abnormal development of cranial neural crest cells-and the most plausible hypothesis is the vascular abnormality and hemorrhage model These 3 models are interrelated, and none of them is completely concordant with all the variable manifestations of HFM External environmental factors (eg, thalidomide, triazene, retinoic acid, and vasoactive medications), maternal intrinsic factors (eg, maternal diabetes), and genetic factors (eg, the recently reported mutations in OTX2, PLCD3, and MYT1) may lead to HFM through ≥1 of these pathogenic processes Whole genome sequencing to identify additional pathogenic variants, biological functional studies to understand the exact molecular mechanisms, and additional animal model and clinical studies with large stratified samples to elucidate the pathogenesis of HFM will be necessary Small-molecule drugs, as well as CRISPR/CAS9-based genetic interventions, for the prevention and treatment of HFM may also be a future research hotspot

Etiology and Pathogenesis of Hemifacial Microsomia

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. Despite being a common congenital facial anomaly, the genetic etiology of craniofacial microsomia (CFM) is not well understood. Here, the authors use exome and genome sequencing of 146 individuals with CFM to identify haploinsufficient variants in SF3B2 as a prevalent underlying cause.

/pdf/haploinsufficiency-of-sf3b2-causes-craniofacial-microsomia-4uffydegix.pdf

Haploinsufficiency of SF3B2 causes craniofacial microsomia.

Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder characterized by hemifacial microsomia associated with ear, eyes and vertebrae malformations showing highly variable expressivity. Recently, MYT1, encoding the myelin transcription factor 1, was reported as the first gene involved in OAVS, within the retinoic acid (RA) pathway. Fifty-seven OAVS patients originating from Brazil were screened for MYT1 variants. A novel de novo missense variant affecting function, c.323C>T (p.(Ser108Leu)), was identified in MYT1, in a patient presenting with a severe form of OAVS. Functional studies showed that MYT1 overexpression downregulated all RA receptors genes (RARA, RARB, RARG), involved in RA-mediated transcription, whereas no effect was observed on CYP26A1 expression, the major enzyme involved in RA degradation, Moreover, MYT1 variants impacted significantly the expression of these genes, further supporting their pathogenicity. In conclusion, a third variant affecting function in MYT1 was identified as a cause of OAVS. Furthermore, we confirmed MYT1 connection to RA signaling pathway.

/pdf/a-novel-de-novo-mutation-in-myt1-the-unique-oavs-gene-4goafwc1zj.pdf

A novel de novo mutation in MYT1 , the unique OAVS gene identified so far

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.

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

Background Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder involving first and second branchial arches derivatives, mainly characterised by asymmetric ear anomalies, hemifacial microsomia, ocular defects and vertebral malformations. Although numerous chromosomal abnormalities have been associated with OAVS, no causative gene has been identified so far. Objectives We aimed to identify the first causative gene for OAVS. Methods As sporadic cases are mostly described in Goldenhar syndrome, we have performed whole exome sequencing (WES) on selected affected individuals and their unaffected parents, looking for de novo mutations. Candidate gene was tested through transient knockdown experiment in zebrafish using a morpholino-based approach. A functional test was developed in cell culture in order to assess deleterious consequences of mutations. Results By WES, we identified a heterozygous nonsense mutation in one patient in the myelin transcription factor 1 ( MYT1 ) gene. Further, we detected one heterozygous missense mutation in another patient among a cohort of 169 patients with OAVS. This gene encodes the MYT1 . Functional studies by transient knockdown of myt1a , homologue of MYT1 in zebrafish, led to specific craniofacial cartilage alterations. Treatment with all-trans retinoic acid (RA), a known teratogenic agent causing OAVS, led to an upregulation of cellular endogenous MYT1 expression. Additionally, cellular wild-type MYT1 overexpression induced a downregulation of RA receptor β ( RARB) , whereas mutated MYT1 did not. Conclusion We report MYT1 as the first gene implicated in OAVS, within the RA signalling pathway.

https://jmg.bmj.com/content/jmedgenet/53/11/752.full.pdf

Mutations in MYT1, encoding the myelin transcription factor 1, are a rare cause of OAVS

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Mutations in MYT1, encoding the myelin transcription factor 1, are a rare cause of OAVS