More evidence on TRIO missense mutations in the spectrin repeat domain causing severe developmental delay and recognizable facial dysmorphism with macrocephaly

Abstract BACKGROUND Alternating Hemiplegia of Childhood (AHC) is an uncommon and complex disorder characterized by age of onset before 18 months, recurrent hemiplegia of one or either sides of the body or quadriplegia. Neurological comorbidities observed in two couples of AHC affected children are here reported together with data drawn by literature review. Results of genetic analysis obtained in the probands are also discussed. Developmental delay, epilepsy, tonic or dystonic spells, nystagmus and autonomic manifestations are frequently reported. AHC is mainly caused by mutations in ATP1A3 gene, and to a lesser extent in ATP1A2 gene.CASE PRESENTATION Clinical and genetic findings of a couple of twins and a couple of siblings affected by AHC from two different Italian families were deeply examined. Intrafamilial clinical variability was shown in the present cases. A pathogenic variant rs606231437 in ATP1A3 gene was detected in twins. For the affected siblings of family 2, the genetic results showed that the older brother and the healthy father shared a novel variant of GRIN2A (c.3175T>A) gene, and two missense mutations in SCNIB (rs150721582) and KCNQ2 (rs771211103) genes. In the younger brother was found only the GRIN2A variant.CONCLUSIONS Developmental delay, epileptic seizures and motor dysfunction are features frequently associated to paroxysmal hemiplegic attacks. Hemiplegic episode is only a sign even if the most remarkable of several neurological comorbidities in AHC carriers. The comparison of molecular analysis among the four probands brings out how the genetic framework is not recurrent, but may result from an unexpected greater genetic heterogeneity.

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Complex Small Supernumerary Marker Chromosome Leading to Partial 4q/21q Duplications: Clinical Implication and Review of the Literature

Cytogenetic and Genome Research ◽

10.1159/000494682 ◽

2018 ◽

Vol 156 (4) ◽

pp. 173-178 ◽

Cited By ~ 1

Author(s):

Fernanda T. Bellucco ◽

Rodrigo A. Fock ◽

Hélio R. de Oliveira-Júnior ◽

Ana B. Perez ◽

Maria I. Melaragno

Keyword(s):

Genetic Counseling ◽

Developmental Delay ◽

Clinical Implication ◽

Marker Chromosome ◽

Accurate Diagnosis ◽

Facial Dysmorphism ◽

Review Of The Literature ◽

Small Supernumerary Marker Chromosome ◽

Wide Range ◽

Similar Phenotype

Complex small marker chromosomes (sSMCs) consist of chromosomal material derived from more than 1 chromosome. Complex sSMCs derived from chromosomes 4 and 21 are rare, with only 7 cases reported. Here, we describe a patient who presented with a complex sSMC derived from a maternal translocation between chromosomes 4 and 21, which was revealed by G-banding, MLPA, and array techniques. The marker chromosome der(21)t(4;21)(q32.1; q21.2)mat is composed of a 25.6-Mb 21pterq21.2 duplication and a 32.1-Mb 4q32.1q35.2 duplication. In comparison to patients with sSMCs derived from chromosomes 4 and 21, our patient showed a similar phenotype with neuropsychomotor developmental delay and facial dysmorphism as the most important finding, being a composition of the findings found in pure 4q and 21q duplications. The wide range of phenotypes associated with sSMCs emphasizes the importance of detailed cytogenomic analyses for an accurate diagnosis, prognosis, and genetic counseling.

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Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability

Journal of Medical Genetics ◽

10.1136/jmedgenet-2017-104620 ◽

2017 ◽

Vol 55 (1) ◽

pp. 28-38 ◽

Cited By ~ 16

Author(s):

Mark J Hamilton ◽

Richard C Caswell ◽

Natalie Canham ◽

Trevor Cole ◽

Helen V Firth ◽

...

Keyword(s):

Congenital Heart Disease ◽

Heart Disease ◽

Intellectual Disability ◽

Protein Kinase ◽

Developmental Delay ◽

Congenital Heart ◽

Kinase Domain ◽

Dominant Negative ◽

Missense Mutations ◽

Protein Kinase Domain

IntroductionRecent evidence has emerged linking mutations in CDK13 to syndromic congenital heart disease. We present here genetic and phenotypic data pertaining to 16 individuals with CDK13 mutations.MethodsPatients were investigated by exome sequencing, having presented with developmental delay and additional features suggestive of a syndromic cause.ResultsOur cohort comprised 16 individuals aged 4–16 years. All had developmental delay, including six with autism spectrum disorder. Common findings included feeding difficulties (15/16), structural cardiac anomalies (9/16), seizures (4/16) and abnormalities of the corpus callosum (4/11 patients who had undergone MRI). All had craniofacial dysmorphism, with common features including short, upslanting palpebral fissures, hypertelorism or telecanthus, medial epicanthic folds, low-set, posteriorly rotated ears and a small mouth with thin upper lip vermilion. Fifteen patients had predicted missense mutations, including five identical p.(Asn842Ser) substitutions and two p.(Gly717Arg) substitutions. One patient had a canonical splice acceptor site variant (c.2898–1G>A). All mutations were located within the protein kinase domain of CDK13. The affected amino acids are highly conserved, and in silico analyses including comparative protein modelling predict that they will interfere with protein function. The location of the missense mutations in a key catalytic domain suggests that they are likely to cause loss of catalytic activity but retention of cyclin K binding, resulting in a dominant negative mode of action. Although the splice-site mutation was predicted to produce a stable internally deleted protein, this was not supported by expression studies in lymphoblastoid cells. A loss of function contribution to the underlying pathological mechanism therefore cannot be excluded, and the clinical significance of this variant remains uncertain.ConclusionsThese patients demonstrate that heterozygous, likely dominant negative mutations affecting the protein kinase domain of the CDK13 gene result in a recognisable, syndromic form of intellectual disability, with or without congenital heart disease.

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Recurrent GNAO1 Mutations Associated With Developmental Delay and a Movement Disorder

Journal of Child Neurology ◽

10.1177/0883073816666474 ◽

2016 ◽

Vol 31 (14) ◽

pp. 1598-1601 ◽

Cited By ~ 22

Author(s):

Leonie A. Menke ◽

Marc Engelen ◽

Mariel Alders ◽

Vincent J. J. Odekerken ◽

Frank Baas ◽

...

Keyword(s):

Movement Disorder ◽

Missense Mutation ◽

Developmental Delay ◽

Recurrence Risk ◽

Epileptic Encephalopathy ◽

Missense Mutations ◽

Phenotype Correlation ◽

Affected Child ◽

Sibling Pairs ◽

Hyperkinetic Movement Disorder

In 2 unrelated patients with axial hypotonia, developmental delay and a hyperkinetic movement disorder, a missense mutation was found in codon 209 of the GNAO1 gene. From the still scarce literature on GNAO1 mutations, a clear genotype-phenotype correlation emerged. From the 26 patients reported thus far, 12 patients had epileptic encephalopathy, and 14 had a developmental delay and a hyperkinetic movement disorder. All but 1 of the latter patients had missense mutations in GNAO1 codon 209 or 246, which thus appear to be mutation hotspots. At least 2 sibling pairs showed that the recurrence risk after 1 affected child with a GNAO1 mutation might be relatively high (5-15%), due to apparent gonadal mosaicism in the parents.

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Monozygotic twins with a de novo 0.32 Mb 16q24.3 deletion, includingTUBB3 presenting with developmental delay and mild facial dysmorphism but without overt brain malformation

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.37227 ◽

2015 ◽

Vol 167 (11) ◽

pp. 2731-2736 ◽

Cited By ~ 6

Author(s):

Sabine Grønborg ◽

Susanne Kjaergaard ◽

Hanne Hove ◽

Vibeke André Larsen ◽

Maria Kirchhoff

Keyword(s):

Developmental Delay ◽

De Novo ◽

Monozygotic Twins ◽

Facial Dysmorphism ◽

Brain Malformation

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Clinical Characteristics and Genotype–Phenotype Correlation in Children with KMT2E Gene-Related Neurodevelopmental Disorders: Report of Two New Cases and Review of Published Literature

Neuropediatrics ◽

10.1055/s-0040-1715629 ◽

2020 ◽

Author(s):

Indar Kumar Sharawat ◽

Prateek Kumar Panda ◽

Lesa Dawman

Keyword(s):

Developmental Delay ◽

Neurodevelopmental Disorder ◽

Copy Number Variants ◽

Cerebral White Matter ◽

Global Developmental Delay ◽

Missense Mutations ◽

Search Terms ◽

Pathogenic Factors ◽

The Common ◽

Variable Combination

Abstract Background In recent years, many new candidate genes are being identified as putative pathogenic factors in children with developmental delay and autism. Recently, heterozygous mutations in the KMT2E gene have been identified as a cause of a unique neurodevelopmental disorder with variable combination of global developmental delay or isolated speech delay, intellectual disability, autistic features, and seizures. Methods Here, we present two new cases of KMT2E mutation-associated neurodevelopmental disorder in a 4-year-old girl and 5-year-old boy. We also performed a pooled review of the previously published cases of KMT2E-related neurodevelopmental disorder. Articles were identified through search engines using appropriate search terms. Results Along with the presented 2 cases, 40 cases were analyzed. Out of them, 30, 6, and 4 children had protein-truncating mutations, missense mutations, and copy number variants, respectively. The common features were global developmental delay (97%) followed by macrocephaly (35%), seizures (30%), and autism (25%). Children with missense variants had severe phenotype, with microcephaly, profound developmental delay, and increased frequency of seizures. Neuroimaging revealed nonspecific changes, including cerebral white matter signal abnormalities. Conclusion KMT2E-related neurodevelopmental disorder remains one of the clinical differentials in children with global developmental delay and/or autistic features/seizure. With the reporting of more cases in the future, the already heterogeneous clinical spectrum of this disease is likely to be widened.

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