De novo EEF1A2mutations in patients with characteristic facial features, intellectual disability, autistic behaviors and epilepsy

The MED13L-related intellectual disability or MRFACD syndrome (Mental retardation and distinctive facial features with or without cardiac defects; MIM # 616789) is one of the most common form of syndromic intellectual disability with about a hundred cases reported so far. Affected individuals share overlapping features comprising intellectual disability, hypotonia, motor delay, remarkable speech delay, and a recognizable facial gestalt. De novo disruption of the MED13L gene by deletions, duplications or sequence variants has been identified deleterious. Siblings affected by intragenic deletion transmitted from a mosaic parent have been reported once in the literature. We now present the first case of paternal germinal mosaicism for a missense MED13L variant causing MRFACD syndrome in one of the father's children and be the likely cause of intellectual disability and facial dysmorphism in the other. As part of the Mediator complex, the MED proteins have an essential role in regulating transcription. 32 subunits of the Mediator complex genes have been linked to congenital malformations that are now acknowledged as transcriptomopathies. The MRFACD syndrome has been suggested to represent a recognizable phenotype.

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The first familial NSD2 cases with a novel variant in a Chinese father and daughter with atypical WHS facial features and a 7.5-year follow-up of growth hormone therapy

BMC Medical Genomics ◽

10.1186/s12920-020-00831-9 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Xuyun Hu ◽

Di Wu ◽

Yuchuan Li ◽

Liya Wei ◽

Xiaoqiao Li ◽

...

Keyword(s):

Growth Hormone ◽

Intellectual Disability ◽

Hormone Therapy ◽

De Novo ◽

Growth Hormone Therapy ◽

Chinese Family ◽

Facial Dysmorphism ◽

Facial Features ◽

Loss Of Function ◽

Genomic Disorder

Abstract Background Wolf-Hirschhorn syndrome is a well-characterized genomic disorder caused by 4p16.3 deletions. Wolf-Hirschhorn syndrome patients exhibit characteristic facial dysmorphism, growth retardation, developmental delay, intellectual disability and seizure disorders. Recently, NSD2 gene located within the 165 kb Wolf-Hirschhorn syndrome critical region was identified as the key causal gene responsible for most if not all phenotypes of Wolf-Hirschhorn syndrome. So far, eight NSD2 loss of function variants have been reported in patients from different parts of the world, all were de novo variants. Methods In our study, we performed whole exome sequencing for two patients from one family. We also reviewed more NSD2 mutation cases in pervious literature. Results A novel loss of function NSD2 variant, c.1577dupG (p.Asn527Lysfs*14), was identified in a Chinese family in the proband and her father both affected with intellectual disability. After reviewing more NSD2 mutation cases in pervious literature, we found none of them had facial features that can be recognized as Wolf-Hirschhorn syndrome. In addition, we have given our proband growth hormone and followed up with this family for 7.5 years. Conclusions Here we reported the first familial NSD2 variant and the long-term effect of growth hormone therapy for patients. Our results suggested NSD2 mutation might cause a distinct intellectual disability and short stature syndrome.

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Tatton-Brown-Rahman syndrome with a novel DNMT3A mutation presented severe intellectual disability and autism spectrum disorder

Human Genome Variation ◽

10.1038/s41439-020-0102-6 ◽

2020 ◽

Vol 7 (1) ◽

Cited By ~ 1

Author(s):

Takayuki Yokoi ◽

Yumi Enomoto ◽

Takuya Naruto ◽

Kenji Kurosawa ◽

Norimichi Higurashi

Keyword(s):

Autism Spectrum Disorder ◽

Intellectual Disability ◽

Developmental Disorders ◽

De Novo ◽

Autism Spectrum ◽

Spectrum Disorder ◽

De Novo Mutation ◽

Facial Features ◽

Severe Intellectual Disability ◽

Dominant Disease

AbstractTatton-Brown-Rahman syndrome is a congenital anomaly syndrome that manifests with overgrowth, macrocephaly, and characteristic facial features. This autosomal dominant disease is caused by a germline mutation in DNMT3A. Some patients with this syndrome develop mild to severe intellectual disability, which is sometimes accompanied by autism spectrum disorder or other developmental disorders. We report a Japanese patient with severe intellectual disability and autism spectrum disorder with a de novo mutation in the active domain of DNMT3A.

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A de novo microdeletion in NRXN1 in a Dutch patient with mild intellectual disability, microcephaly and gonadal dysgenesis

Genetics Research ◽

10.1017/s001667231500021x ◽

2015 ◽

Vol 97 ◽

Author(s):

ZEHRA AGHA ◽

ZAFAR IQBAL ◽

TJITSKE KLEEFSTRA ◽

CHRISTIANE ZWEIER ◽

ROLPH PFUNDT ◽

...

Keyword(s):

Intellectual Disability ◽

Gonadal Dysgenesis ◽

Psychotic Disorders ◽

De Novo ◽

Pathogenic Mutation ◽

Facial Features ◽

Mild Intellectual Disability ◽

Dutch Patient ◽

Prepubertal Age ◽

Female Carriers

SummaryThis report is regarding a Dutch female with microcephaly, mild intellectual disability (ID), gonadal dysgenesis and dysmorphic facial features with synophrys. Upon genotyping, an ~455 kb de novo deletion encompassing the first exon of NRXN1 was found. Bidirectional sequencing of the coding exons of the NRXN1 alpha isoform was subsequently performed to investigate the possibility of a pathogenic mutation on the other allele, but we could not find any other mutation. Previously, many heterozygous mutations as well as microdeletions in NRXN1 were shown to be associated with ID, autism, schizophrenia, and other psychiatric and psychotic disorders. Our results are in agreement with other reports that show that NRXN1 deletions can lead to ID, microcephaly and mild dysmorphic features. However, this is the first report of gonadal dysgenesis being associated with such deletions. It is not clear whether there is a causal relationship between the NRXN1 deletion and gonadal dysgenesis, but it is of interest that the FSHR gene, which encodes the follicle-stimulating hormone receptor causative correlation that is mutated in ovarian dysgenesis, is located proximal to the NRXN1 gene. Given that most of the females carrying NRXN1 deletions have been diagnosed at a prepubertal age, gynecologic screening of female carriers of a NRXN1 deletion is warranted.

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De novo pathogenic variants inCHAMP1are associated with global developmental delay, intellectual disability, and dysmorphic facial features

Molecular Case Studies ◽

10.1101/mcs.a000661 ◽

2015 ◽

Vol 2 (1) ◽

pp. a000661 ◽

Cited By ~ 14

Author(s):

Akemi J. Tanaka ◽

Megan T. Cho ◽

Kyle Retterer ◽

Julie R. Jones ◽

Catherine Nowak ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

De Novo ◽

Global Developmental Delay ◽

Facial Features ◽

Pathogenic Variants

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The int22h1/int22h2-Mediated Xq28 Duplication Syndrome: An Intersection between Neurodevelopment, Immunology, and Cancer

Genes ◽

10.3390/genes12060860 ◽

2021 ◽

Vol 12 (6) ◽

pp. 860

Author(s):

Rami A. Ballout ◽

Ayman W. El-Hattab

Keyword(s):

Intellectual Disability ◽

X Chromosome ◽

Potential Role ◽

Pediatric Patients ◽

De Novo ◽

Facial Features ◽

Immunological Responses ◽

Xq28 Duplication ◽

Duplication Syndrome

The int22h1/int22h2-mediated Xq28 duplication syndrome is a rare X-linked intellectual disability syndrome (XLIDS) arising from a duplication of the segment between intron 22 homologous regions 1 and 2, on the q28 subregion of the X chromosome. The main clinical features of the syndrome include intellectual disability, neurobehavioral abnormalities, and dysmorphic facial features. Due to the X-linked nature of the syndrome, affected males exhibit more severe phenotypes compared with heterozygous females. A unique distinguishing feature of the syndrome across the sexes, however, is a peculiar combination of recurrent sinopulmonary infections and atopy exclusively seen in a subset of affected males. In addition to the ‘typical’ 0.5 Mb duplication detected in most cases reported to date with the syndrome, a shortened centromeric version, and another 0.2 Mb telomerically shifted one, have been recently identified, with most detected duplications being maternally inherited, except for three recent cases found to have de novo duplications. Interestingly, a recently reported case of an affected male suggests a possible association of the syndrome with multiple malignancies, an observation that has been recently replicated in two pediatric patients. As a result, a better understanding of the pathogenesis of int22h1/int22h2-mediated Xq28 duplication syndrome may grant us a better understanding of the sex-specific differences in immunological responses, as well as the potential role of the genes involved by the duplication, in oncogenesis.

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A novel de novo DDX3X missense variant in a female with brachycephaly and intellectual disability: a case report

Italian Journal of Pediatrics ◽

10.1186/s13052-021-01033-4 ◽

2021 ◽

Vol 47 (1) ◽

Author(s):

Giada Moresco ◽

Jole Costanza ◽

Carlo Santaniello ◽

Ornella Rondinone ◽

Federico Grilli ◽

...

Keyword(s):

Intellectual Disability ◽

Clinical Presentation ◽

De Novo ◽

Clinical Signs ◽

Missense Variant ◽

Psychomotor Development ◽

Helicase Domain ◽

Protein Activity ◽

Mrna Metabolism ◽

Pathogenic Variants

Abstract Background De novo pathogenic variants in the DDX3X gene are reported to account for 1–3% of unexplained intellectual disability (ID) in females, leading to the rare disease known as DDX3X syndrome (MRXSSB, OMIM #300958). Besides ID, these patients manifest a variable clinical presentation, which includes neurological and behavioral defects, and abnormal brain MRIs. Case presentation We report a 10-year-old girl affected by delayed psychomotor development, delayed myelination, and polymicrogyria (PMG). We identified a novel de novo missense mutation in the DDX3X gene (c.625C > G) by whole exome sequencing (WES). The DDX3X gene encodes a DEAD-box ATP-dependent RNA-helicase broadly implicated in gene expression through regulation of mRNA metabolism. The identified mutation is located just upstream the helicase domain and is suggested to impair the protein activity, thus resulting in the altered translation of DDX3X-dependent mRNAs. The proband, presenting with the typical PMG phenotype related to the syndrome, does not show other clinical signs frequently reported in presence of missense DDX3X mutations that are associated with a most severe clinical presentation. In addition, she has brachycephaly, never described in female DDX3X patients, and macroglossia, that has never been associated with the syndrome. Conclusions This case expands the knowledge of DDX3X pathogenic variants and the associated DDX3X syndrome phenotypic spectrum.

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Clinical characteristics of Polish patients with molecularly confirmed Mowat-Wilson syndrome

Journal of Applied Genetics ◽

10.1007/s13353-021-00636-1 ◽

2021 ◽

Author(s):

Aleksandra Jakubiak ◽

Krzysztof Szczałuba ◽

Magdalena Badura-Stronka ◽

Anna Kutkowska-Kaźmierczak ◽

Anna Jakubiuk-Tomaszuk ◽

...

Keyword(s):

Intellectual Disability ◽

Congenital Anomalies ◽

Chromosomal Region ◽

Neurodevelopmental Disorder ◽

Hirschsprung Disease ◽

Psychomotor Retardation ◽

Facial Features ◽

Dysmorphic Features ◽

Pathogenic Variants ◽

Intragenic Deletions

AbstractMowat-Wilson syndrome is a rare neurodevelopmental disorder caused by pathogenic variants in the ZEB2 gene, intragenic deletions of the ZEB2 gene, and microdeletions in the critical chromosomal region 2q22-23, where the ZEB2 gene is located. Mowat-Wilson syndrome is characterized by typical facial features that change with the age, severe developmental delay with intellectual disability, and multiple congenital abnormalities. The authors describe the clinical and genetic aspects of 28th patients with Mowat-Wilson syndrome diagnosed in Poland. Characteristic dysmorphic features, psychomotor retardation, intellectual disability, and congenital anomalies were present in all cases. The incidence of most common congenital anomalies (heart defect, Hirschsprung disease, brain defects) was similar to presented in literature. Epilepsy was less common compared to previously reported cases. Although the spectrum of disorders in patients with Mowat-Wilson syndrome is wide, knowledge of characteristic dysmorphic features awareness of accompanying abnormalities, especially intellectual disability, improves detection of the syndrome.

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