Exome sequencing identifies compound heterozygous mutations in <i>C12orf57</i> in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures

Platzer, Konrad; Hüning, Irina; Obieglo, Carolin; Schwarzmayr, Thomas; Gabriel, Rainer; Strom, Tim M.; Gillessen‐Kaesbach, Gabriele; Kaiser, Frank J.

doi:10.1002/ajmg.a.36592

Cited by 9 publications

(5 citation statements)

References 10 publications

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“…Although the structure and function of its product are not known, biallelic variants in C12orf57 have been identified in familial and sporadic cases of microphthalmia with bilateral iris and/or chorioretinal coloboma (Patel et al 2018;Platzer et al 2014;Zahrani et al 2013), unilateral iris or chorioretinal coloboma and posterior staphyloma (Salih et al 2013), and microcornea with corneal opacity and dense cataract (Salih et al 2013). Additional neurologic features have been observed, such as global developmental delay and epilepsy, corpus callosum anomalies and behavioral difficulties, consistent with Temtamy syndrome (MIM#218340).…”

Section: C12orf57 (Chromosome 12 Open Reading Frame 57)mentioning

confidence: 99%

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

et al. 2019

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Eye formation is the result of coordinated induction and differentiation processes during embryogenesis. Disruption of any one of these events has the potential to cause ocular growth and structural defects, such as anophthalmia and microphthalmia (A/M). A/M can be isolated or occur with systemic anomalies, when they may form part of a recognizable syndrome. Their etiology includes genetic and environmental factors; several hundred genes involved in ocular development have been identified in humans or animal models. In humans, around 30 genes have been repeatedly implicated in A/M families, although many other genes have been described in single cases or families, and some genetic syndromes include eye anomalies occasionally as part of a wider phenotype. As a result of this broad genetic heterogeneity, with one or two notable exceptions, each gene explains only a small percentage of cases. Given the overlapping phenotypes, these genes can be most efficiently tested on panels or by whole exome/genome sequencing for the purposes of molecular diagnosis. However, despite whole exome/genome testing more than half of patients currently remain without a molecular diagnosis. The proportion of undiagnosed cases is even higher in those individuals with unilateral or milder phenotypes. Furthermore, even when a strong gene candidate is available for a patient, issues of incomplete penetrance and germinal mosaicism make diagnosis and genetic counselling challenging. In this review, we present the main genes implicated in nonsyndromic human A/M phenotypes and, for practical purposes, classify them according to the most frequent or predominant phenotype each is associated with. Our intention is that this will allow clinicians to rank and prioritize their molecular analyses and interpretations according to the phenotypes of their patients.

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Section: C12orf57 (Chromosome 12 Open Reading Frame 57)mentioning

confidence: 99%

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

et al. 2019

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“…Temtamy syndrome is an extremely rare disorder, and only a limited number of studies have been conducted (1)(2)(3)(4)(5)(6)(7). The present study reports the first East Asian patient with a novel C12orf57 homozygous pathogenic variant; all other heterozygous carriers in the family were clinically healthy.…”

Section: Discussionmentioning

confidence: 68%

“…In 2013, pathogenic variants of C12orf57 were first reported to cause Temtamy syndrome (3,4). At the present time, only seven pathogenic variants have been illustrated (1)(2)(3)(4)(5)(6). Those of Middle Eastern descent are particularly susceptible to C12orf57 pathogenic variants, with 54/56 (96.4%) of all the reported patients from Middle Eastern countries, predominantly Saudi Arabia (3)(4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Temtamy syndrome caused by a new C12orf57 variant in a Chinese boy, including pedigree analysis and literature review

Wang

Luo

et al. 2019

Exp Ther Med

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Temtamy syndrome is an extremely rare disorder caused by chromosome 12 open reading frame 57 (C12orf57) pathogenic variants. The present study reported a boy with Temtamy syndrome displaying global developmental delay, epilepsy and dysmorphic facial appearance. Whole-exome sequencing was performed to identify a novel homozygous pathogenic variant of C12orf57 (c.3G >C, p.Met1IIe), and the affected protein structure and function were predicted to be pathogenic. Additionally, clinical features of the other reported 56 patients with C12orf57 pathogenic variants were reviewed and compared. This study highlighted that C12orf57 pathogenic variants are mainly associated with global developmental delay, epilepsy and dysmorphic facial appearances. The clinical features were in accordance with the previously reported cases, except for those with recurrent infection, but without corpus callosum abnormalities. The present study reported the first Asian case to the best of our knowledge with Temtamy syndrome, and the novel C12orf57 pathogenic variant has not reported in any ethnic groups previously. The present study expanded the spectrum of C12orf57 pathogenic variants as well as the ethnic backgrounds of the affected patients.

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“…Exome sequencing studies identified homozygous and compound heterozygous mutations in C12orf57 to cause an autosomal recessive syndromic form of intellectual disability with ACC. C12orf57 is a highly conserved gene and is required for the development of the human corpus callosum [Akizu et al, 2013;Platzer et al, 2014].…”

Section: Discussionmentioning

confidence: 99%

Pre- and Postnatal Analysis of Chromosome 1q44 Deletion in Agenesis of Corpus Callosum

et al. 2015

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Agenesis of corpus callosum (ACC) is one of the common brain abnormalities and also a common finding in children with mental disability. ACC is heterogeneous and can occur as an isolated condition or as part of a syndrome. ACC can be accurately identified by the absence of the cavum septum pallucidum and tear drop effect of the lateral ventricle after 18 weeks of pregnancy in an ultrasound scan. Genetic causes have been attributed to 30-45% of cases with ACC. Submicroscopic deletions of 1q43q44 have been reported in several cases of ACC. The AKT3 gene, mapped to 1q44, is required for the development of the callosum and brain size. It is considered to be a candidate gene for ACC. We studied a total of 22 cases with ACC, in pre- and postnatal samples using FISH probes. None of the samples showed a deletion in 1q44, implying that the AKT3 gene may not be associated with ACC.

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Exome sequencing identifies compound heterozygous mutations in C12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures

Cited by 9 publications

References 10 publications

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

Temtamy syndrome caused by a new C12orf57 variant in a Chinese boy, including pedigree analysis and literature review

Pre- and Postnatal Analysis of Chromosome 1q44 Deletion in Agenesis of Corpus Callosum

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