Pericentric inversion, inv(14)(p11.2q22.3), in a 9-month old with features of Goldenhar syndrome

Northup, Jill K.; Matalon, Dena; Hawkins, Judy C.; Matalon, Reuben; Velagaleti, Gopalrao V.N.

doi:10.1097/mcd.0b013e3283359386

Cited by 16 publications

(14 citation statements)

References 29 publications

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“…Interestingly, the proband suffered a range of clinical signs resembling HFM, including facial asymmetry, mandibular hypoplasia, and ear defects in addition to developmental delay, lacrimal duct stenosis, and renal anomalies. Northup et al [32] reported a large pericentric inversion inv(14)(p11.2q22.3) in a proband with HFM signs, inherited from his phenotypically normal mother. Ballesta-Martinez et al [33] recently published a clinical report of a 14q22 duplication in a Spanish family with variable phenotypes resembling HFM.…”

Section: Resultsmentioning

confidence: 99%

OTX2 Duplication Is Implicated in Hemifacial Microsomia

et al. 2014

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Hemifacial microsomia (HFM) is the second most common facial anomaly after cleft lip and palate. The phenotype is highly variable and most cases are sporadic. We investigated the disorder in a large pedigree with five affected individuals spanning eight meioses. Whole-exome sequencing results indicated the absence of a pathogenic coding point mutation. A genome-wide survey of segmental variations identified a 1.3 Mb duplication of chromosome 14q22.3 in all affected individuals that was absent in more than 1000 chromosomes of ethnically matched controls. The duplication was absent in seven additional sporadic HFM cases, which is consistent with the known heterogeneity of the disorder. To find the critical gene in the duplicated region, we analyzed signatures of human craniofacial disease networks, mouse expression data, and predictions of dosage sensitivity. All of these approaches implicated OTX2 as the most likely causal gene. Moreover, OTX2 is a known oncogenic driver in medulloblastoma, a condition that was diagnosed in the proband during the course of the study. Our findings suggest a role for OTX2 dosage sensitivity in human craniofacial development and raise the possibility of a shared etiology between a subtype of hemifacial microsomia and medulloblastoma.

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Section: Resultsmentioning

confidence: 99%

OTX2 Duplication Is Implicated in Hemifacial Microsomia

et al. 2014

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“…Familial instances compatible with autosomal dominant inheritance have been observed [Tasse et al, ; Vendramini‐Pittoli and Kokitsu‐Nakata, ] in about 2–10% of cases. Linkage analysis in families with autosomal dominant inheritance and array‐CGH analysis have detected candidate loci for OAVS offering new insights into the understanding of pathogenesis of this entity [Kelberman et al, ; Callier et al, ; Ou et al, ; Rooryck et al, ; Huang et al, ; Northup et al, ; Rooryck et al, ].…”

Section: Introductionmentioning

confidence: 99%

Autosomal dominant oculoauriculovertebral spectrum and 14q23.1 microduplication

Ballesta-Martínez

López‐González

Dulcet³

et al. 2013

American J of Med Genetics Pt A

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Oculoauriculovertebral spectrum (OAVS; OMIM 164210) is characterized by anomalies derived from an abnormal development of the first and second branchial arches, with marked inter and intra-familial phenotypic variability. Main clinical features are defects on aural, oral, mandibular, and vertebral development. Cardiac, pulmonary, renal, skeletal, and central nervous system anomalies have also been described. Most affected individuals are isolated cases in otherwise normal families. Autosomal dominant inheritance has been observed in about 2-10% of cases and linkage analysis as well as array-CGH analysis have detected candidate loci for OAVS offering new insights into the understanding of pathogenesis of this entity. We describe a family with clinical diagnosis of OAVS, autosomal dominant inheritance pattern, and detection of a 14q23.1 duplication of 1.34 Mb in size which segregates with the phenotype. This region contains OTX2, which is involved in the development of the forebrain, eyes, and ears, and appears to be a good candidate gene for OAVS.

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“…Interestingly, the proband suffered a range of clinical signs resembling HFM including facial asymmetry, mandibular hypoplasia, and ear defects in addition to developmental delay, lacrimal duct stenosis and renal anomalies. Northup et al [32] reported a large pericentric inversion inv(14)(p11.2q22.3) in a proband with HFM signs, inherited from his phenotypically normal mother. Ballesta-Martinez et al [33] recently published a short clinical report of a 14q22 duplication in a Spanish family with variable phenotypes resembling HFM.…”

Section: Resultsmentioning

confidence: 99%

OTX2 Dosage Sensitivity is Implicated in Hemifacial Microsomia

Zielinski

Markus

Sheikh

et al. 2013

Preprint

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Hemifacial microsomia (HFM) is the second most common facial anomaly after cleft lip and palate. The phenotype is highly variable and most cases are sporadic. Here, we investigated the disorder in a large pedigree with five affected individuals spanning eight meioses. We performed whole-exome sequencing and a genome-wide survey of segmental variations. Analysis of the exome sequencing results indicated the absence of a pathogenic coding point mutation. Inspection of segmental variations identified a 1.3Mb duplication of chromosome 14q22.3 in all affected individuals that was absent in more than 1000 chromosomes of ethnically matched controls. The duplication was absent in seven additional sporadic HFM cases, which is concordant with the known heterogeneity of the disorder. To find the critical gene in the duplicated region, we analyzed signatures of human craniofacial disease networks, mouse expression data, and predictions of dosage sensitivity. All of these approaches implicated OTX2 as the most likely causal gene. Moreover, OTX2 is a known oncogenic driver in medulloblastoma, a condition that was diagnosed in the proband during the course of our study. Our findings highlight dosage sensitivity of OTX2 in human craniofacial development and suggest a possible shared etiology between a subtype of hemifacial microsomia and medulloblastoma.

show abstract

Pericentric inversion, inv(14)(p11.2q22.3), in a 9-month old with features of Goldenhar syndrome

Cited by 16 publications

References 29 publications

OTX2 Duplication Is Implicated in Hemifacial Microsomia

OTX2 Duplication Is Implicated in Hemifacial Microsomia

Autosomal dominant oculoauriculovertebral spectrum and 14q23.1 microduplication

OTX2 Dosage Sensitivity is Implicated in Hemifacial Microsomia

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