Complex Diagnostics of Non-Specific Intellectual Developmental Disorder

Levchenko, Olga A.; Дадали, Е. Л.; Bessonova, L. A.; Демина, Н. А.; Rudenskaya, G. E.; Matyushchenko, Galina; Маркова, Т. В.; Анисимова, И. В.; Семенова, Н. А.; Щагина, О. А.; Рыжкова, О. П.; Зинченко, Р. А.; Галкина, В. А.; Voinova, Victoria; Nagieva, S. E.; Лавров, А. В.

doi:10.3390/ijms23147764

Cited by 8 publications

(10 citation statements)

References 103 publications

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“…Whole-exome sequencing revealed a previously reported [ 12 ] variant in exon 12 in the DNMT3A gene (hg19—chr2:25468920G>T) in a heterozygous state. This variant is absent in the gnomAD database and leads to the formation of a premature stop codon—c.1443C>A (p.Tyr481Ter).…”

Section: Resultsmentioning

confidence: 99%

Clinical Case of Mild Tatton–Brown–Rahman Syndrome Caused by a Nonsense Variant in DNMT3A Gene

Bostanova,

Levchenko,

Sharova

et al. 2024

Clinics and Practice

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Tatton–Brown–Rahman syndrome is a rare autosomal dominant hereditary disease caused by pathogenic variants in the DNMT3A gene, which is an important participant in epigenetic regulation, especially during embryonic development, and is highly expressed in all tissues. The main features of the syndrome are high growth, macrocephaly, intellectual disability, and facial dysmorphic features. We present a clinical case of Tatton–Brown–Rahman syndrome in a ten-year-old boy with macrocephaly with learning difficulties, progressive eye impairment, and fatigue suspected by a deep learning-based diagnosis assistance system, Face2Gene. The proband underwent whole-exome sequencing, which revealed a recurrent nonsense variant in the 12th exon of the DNMT3A, leading to the formation of a premature stop codon—NM_022552.5:c.1443C>A (p.Tyr481Ter), in a heterozygous state. This variant was not found in parents, confirming its de novo status. The patient case described here contributes to the understanding of the clinical diversity of Tatton–Brown–Raman syndrome with a mild clinical presentation that expands the phenotypic spectrum of the syndrome. We report the first recurrent nonsense variant in the DNMT3A gene, suggesting a mutational hot-spot. Differential diagnoses of this syndrome with Sotos syndrome, Weaver syndrome, and Cowden syndrome, as well as molecular confirmation, are extremely important, since the presence of certain types of pathogenic variants in the DNMT3A gene significantly increases the risk of developing acute myeloid leukemia.

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Section: Resultsmentioning

confidence: 99%

Clinical Case of Mild Tatton–Brown–Rahman Syndrome Caused by a Nonsense Variant in DNMT3A Gene

Bostanova,

Levchenko,

Sharova

et al. 2024

Clinics and Practice

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“…Amino acid residue 130 of PTEN is a site of frequent somatic mutation in cancers of the breast 47 , thyroid 48 , head and neck 49 , and endometrium 50 . p.Arg130Gln, p.Arg130*, and p.Arg335X have been reported in patients with autism-macrocephaly syndrome [51][52][53][54][55][56][57][58] . Notably, these neurosurgically-treated PTEN-mutated probands had no previous diagnosis of PHTS, autismmacrocephaly syndrome, or other cancers before WES.…”

Section: De Novo Pten Mutations In Patients Withmentioning

confidence: 96%

Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

DeSpenza¹,

Kiziltug²,

Allington³

et al. 2023

Preprint

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Expansion of the cerebrospinal fluid (CSF)-filled cerebral ventricles (ventriculomegaly) is the quintessential feature of congenital hydrocephalus (CH) but also seen in autism spectrum disorder (ASD) and several neuropsychiatric diseases. PTEN is frequently mutated in ASD; here, we show PTEN is a bona fide risk gene for the development of ventriculomegaly, including neurosurgically-treated CH. Pten-mutant hydrocephalus is associated with aqueductal stenosis due to the hyperproliferation of periventricular Nkx2.1+ neural precursors (NPCs) and CSF hypersecretion from inflammation-dependent choroid plexus hyperplasia. The hydrocephalic Pten-mutant cortex exhibits ASD-like network dysfunction due to impaired activity of Nkx2.1+ NPC-derived inhibitory interneurons. Raptor deletion or post-natal Everolimus corrects ventriculomegaly, rescues cortical deficits, and increases survival by antagonizing mTORC1-dependent Nkx2.1+ cell pathology. These results implicate a dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of NPCs and their interneuron descendants. These data identify a non-surgical treatment target for hydrocephalus and have implications for other developmental brain disorders.

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“…The top 10 most prevalent DNV among GDD/ID are listed in Table 1 [ 2 ]. Most of the GDD/ID genes discovered were de novo variants (DNV) [ 2 , 8 , 13 , 14 ]. Deletions were more common than duplications, resulting in frameshift, stop-gained, alternative-splice-site, or missense mutations.…”

Section: Genetic Etiologies Of Intellectual Disabilities and Global D...mentioning

confidence: 99%

“…Overall, the diagnostic yield of molecular modalities is positively correlated with the number of dysmorphic features or MCA that are present [ 8 ]. The more profoundly the IQ of an individual is affected, the more likely the ID is to have a genetic etiology.…”

Section: Genetic Etiologies Of Intellectual Disabilities and Global D...mentioning

confidence: 99%

“…Recently, high-throughput sequencing, such as ES or GS, has allowed for rapid, in-depth analysis of the human genome. New evidence is showing support for MPS to replace CMA as the first-tier test for unexplained autistic spectrum disorder, GDD/ID, and MCA [ 6 , 7 , 8 , 9 ]. ACMG has also published an updated guideline to recommend ES and GS as the first-tier genetic evaluation for patients with ID [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Genome-Wide Sequencing Modalities for Children with Unexplained Global Developmental Delay and Intellectual Disabilities—A Narrative Review

Chen

2023

Children

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Unexplained global developmental delay (GDD) and intellectual disabilities (ID) together affect nearly 2% of the pediatric population. Establishing an etiologic diagnosis is crucial for disease management, prognostic evaluation, and provision of physical and psychological support for both the patient and the family. Advancements in genome sequencing have allowed rapid accumulation of gene–disorder associations and have accelerated the search for an etiologic diagnosis for unexplained GDD/ID. We reviewed recent studies that utilized genome-wide analysis technologies, and we discussed their diagnostic yield, strengths, and limitations. Overall, exome sequencing (ES) and genome sequencing (GS) outperformed chromosomal microarrays and targeted panel sequencing. GS provides coverage for both ES and chromosomal microarray regions, providing the maximal diagnostic potential, and the cost of ES and reanalysis of ES-negative results is currently still lower than that of GS alone. Therefore, singleton or trio ES is the more cost-effective option for the initial investigation of individuals with GDD/ID in clinical practice compared to a staged approach or GS alone. Based on these updated evidence, we proposed an evaluation algorithm with ES as the first-tier evaluation for unexplained GDD/ID.

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Complex Diagnostics of Non-Specific Intellectual Developmental Disorder

Cited by 8 publications

References 103 publications

Clinical Case of Mild Tatton–Brown–Rahman Syndrome Caused by a Nonsense Variant in DNMT3A Gene

Clinical Case of Mild Tatton–Brown–Rahman Syndrome Caused by a Nonsense Variant in DNMT3A Gene

Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

Genome-Wide Sequencing Modalities for Children with Unexplained Global Developmental Delay and Intellectual Disabilities—A Narrative Review

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