Atypical, milder presentation in a child with CC2D2A and KIDINS220 variants

Lam, Zena; Albaba, Shadi; Study, Ddd; Balasubramanian, Meena

doi:10.1097/mcd.0000000000000298

Cited by 7 publications

(10 citation statements)

References 42 publications

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“…Congenital heart disease, mainly atrioventricular septal defect, is an additional novel manifestation of KIDINS22-related disorders in humans that was not previously specified (Josifova et al, 2016;Lam et al, 2020;Mero et al, 2017;Yang et al, 2018;Zhao et al, 2019).…”

Section: Discussionmentioning

confidence: 96%

“…Congenital heart disease, mainly atrioventricular septal defect, is an additional novel manifestation of KIDINS22 ‐ related disorders in humans that was not previously specified (Josifova et al, 2016; Lam et al, 2020; Mero et al, 2017; Yang et al, 2018; Zhao et al, 2019). However, Kidins220 knockout mouse embryos displayed severe structural cardiac malformations including enlarged atria, ventricular myocardial wall thinning, defects in the outflow tract, valve malformations, and septal defects and it was speculated that the perinatal lethality in these embryos was owed to early cardiac failure (Cesca et al, 2011, 2012; Marracci, Giannini, Vitiello, Andreazzoli, & Dente, 2013; Schmieg et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Several subsequent reports confirmed that heterozygous truncating variants in the protein's C‐terminus are associated with SINO syndrome. Notably, none of the described patients showed a compromised embryonal/fetal development (Lam, Albaba, Study, & Balasubramanian, 2020; Yang, Zhang, Peng, & Yin, 2018; Zhao et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Prenatal delineation of a distinct lethal fetal syndrome caused by a homozygous truncating KIDINS220 variant

El-Dessouky

Issa

Aboulghar

et al. 2020

American J of Med Genetics Pt A

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Kinase D-interacting substrate of 220 kDa (KIDINS220) is a transmembrane protein playing integral role in growth mediating pathways in the nervous and cardiovascular systems. KIDINS220 heterozygous truncating variants that affect the protein's C-terminus have been associated with a phenotype, so far described only in few unrelated children, including spastic paraplegia, intellectual disability, nystagmus, and obesity. More recently, a homozygous, more N-terminal truncating variant in KIDINS220 gene was suggested to be associated with enlarged cerebral ventricles and limb contractures in three fetuses from a consanguineous family. We confirm the latter finding by presenting the first detailed prenatal identification of a fetal phenotype associated with novel homozygous deleterious frameshift variant in KIDINS220 gene in a consanguineous healthy Egyptian couple. History of unexplained seven miscarriages and a similar stillbirth were recorded. Prenatal ultrasonography revealed limb contractions and ventriculomegaly; in addition to previously unreported cerebellar anomalies, cardiac anomalies and hydrops fetalis. These findings represent an expansion of clinical and molecular spectrum associated with KIDINS220 variants and broaden our understanding of genotype-phenotype relationships in lethal congenital contractures syndromes and associated severe abnormal embryological development. More generally, our study adds KIDINS220 to the rare group of genes which may cause disease by either of two distinct mutational mechanisms.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Prenatal delineation of a distinct lethal fetal syndrome caused by a homozygous truncating KIDINS220 variant

El-Dessouky

Issa

Aboulghar

et al. 2020

American J of Med Genetics Pt A

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“…Mutations in these genes are associated with a spectrum of both overlapping and distinct ciliopathies illustrating the concepts of genetic heterogeneity and pleiotropy, inherent to most ciliopathy genes. To capture the genetic and clinical spectrum of CEP120 -and CC2D2A -associated disease, we reviewed literature, including previous mutation summaries (Bachmann-Gagescu et al, 2012;Lam, Albaba, Study, & Balasubramanian, 2020), and open-access tools to generate a curated, annotated and HGVS compliant database. Furthermore, we used in silico tools to identify tissue-specific basal exon skipping events.…”

Section: Discussionmentioning

confidence: 99%

Update of genetic variants in CEP120 and CC2D2A -- with an emphasis on genotype-phenotype correlations, tissue specific transcripts and exploring mutation specific exon skipping therapies

Gil

Olinger

Ramsbottom

et al. 2020

Preprint

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Mutations in ciliary genes cause a spectrum of both overlapping and distinct clinical syndromes (ciliopathies). CEP120 and CC2D2A are paradigmatic examples for this genetic heterogeneity and pleiotropy as mutations in both cause Joubert syndrome but are also associated with skeletal ciliopathies and Meckel syndrome, respectively. The molecular basis for this phenotypical variability is not understood but basal exon skipping likely contributes to tolerance for deleterious mutations via preservation of the amount of expressed functional protein. Here we systematically review and annotate genetic variants described in CEP120and CC2D2A-associated disease and confirm more severe clinical presentations with biallelic truncating CC2D2A mutations. Combining in silico and ex vivo studies, we identify alternative basal exon skipping in the kidney, with possible relevance for organ-specific disease manifestations. Finally, we propose a multimodal approach to classify exons amenable to exon skipping and by mapping reported variants, 14 truncating mutations in 7 CC2D2A exons were identified as potentially rescuable by targeted exon skipping, an approach that is already in clinical use for other inherited human diseases. We conclude that genotype-phenotype correlations for CC2D2A support the deleteriousness of null alleles and that CC2D2A, but not CEP120, offers potential for therapeutic exon skipping approaches.

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“…WES helps to screen previously reported genes, as well as efficiently identify novel genes. Moreover, WES has improved the genotype–phenotype correlation of CC2D2A variants in complex phenotypes of JBTS, Meckel–Gruber syndrome and other related ciliopathies 8–10 …”

Section: Introductionmentioning

confidence: 99%

Whole exome sequencing identified a novel missense alteration in CC2D2A causing Joubert syndrome 9 in a Pakhtun family

Khan

Latif

Saif

et al. 2020

The Journal of Gene Medicine

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BackgroundJoubert syndrome (JBTS) is a heterogenous disorder characterized by intellectual disability, developmental delays, molar tooth sign in brain imaging, hypotonia, ocular motor apraxia and overlapping features of ciliopathies. There are 36 clinical subtypes of JBTS, with an equal number of genes known so far for this phenotype.MethodsWhole exome sequencing (WES) and Sanger sequencing were performed for the molecular diagnosis of a Pakhtun family affected with Joubert syndrome type 9 (JBTS9).ResultsA novel homozygous missense variant (c.4417C>G; Pro1473Ala) in exon 34 was identified in coiled‐coil and C2 domains‐containing the protein 2A (CC2D2A; NM_001080522) gene. The variant co‐segregated in autosomal recessive fashion within the family and was not found in 200 ethnically matched unaffected individuals. In silico analyses supported the pathogenic effect of the altered CC2D2A protein.ConclusionsTo the best of our knowledge, this is the first report of CC2D2A alteration co‐segragating with a JBTS9 phenotype in a Pakhtun family from Pakistan. Our findings broaden the pathogenic spectrum of JBTS9, adding a novel variant to CC2D2A variation pool. WES analysis is a successful molecular diagnostic tool for rare genetic disorders, especially in those populations where the marriage of cousins is more frequent. Efficient and accurate genetic testing and counselling of the affected families are helpful for patient management and for reducing the disease burden in future generations.

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Atypical, milder presentation in a child with CC2D2A and KIDINS220 variants

Abstract: This is a repository copy of Atypical, milder presentation in a child with CC2D2A and KIDINS220 variants.

Cited by 7 publications

References 42 publications

Prenatal delineation of a distinct lethal fetal syndrome caused by a homozygous truncating KIDINS220 variant

Prenatal delineation of a distinct lethal fetal syndrome caused by a homozygous truncating KIDINS220 variant

Update of genetic variants in CEP120 and CC2D2A -- with an emphasis on genotype-phenotype correlations, tissue specific transcripts and exploring mutation specific exon skipping therapies

Whole exome sequencing identified a novel missense alteration in CC2D2A causing Joubert syndrome 9 in a Pakhtun family

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