Early onset of cardiomyopathy and intellectual disability in a girl with Danon disease associated with a de novo novel mutation of the LAMP2 gene

Abstract Context Luscan-Lumish syndrome (LLS) is characterized by postnatal overgrowth, obesity, Chiari I malformation, seizures, and intellectual disability. SET domain-containing protein 2 (SETD2) is a histone methyltransferase, where mutations in the gene are associated with the development of LLS. However, mechanisms underlying LLS remain unclear. Case description A 20-year-old man was referred to our hospital because of tall stature. His body height was 188.2 cm (+3.18 SD) and he showed obesity with a body mass index of 28.4 kg/m 2. He exhibited acral overgrowth, jaw malocclusion, and prognathism, but no history of seizures, intellectual disability, or speech delay. Serum growth hormone (GH), insulin-like growth factor 1 (IGF-1), and nadir GH levels after administration of 75 g oral glucose were within normal range. Pituitary magnetic resonance imaging showed no pituitary adenoma, but Chiari I malformation. Whole exome sequencing analysis of the proband revealed a de novo heterozygous germline mutation in SETD2 (c.236T>A, p.L79H). Skin fibroblasts derived from the patient grew faster than those from his father and the control subject. In addition, these cells showed enhanced tyrosine phosphorylation and transcriptional activity of signal transducer and activator of transcription 5b (STAT5b) and increased IGF-1 expression induced by GH. Conclusion This is a mild case of LLS with a novel mutation in SETD2 without neurological symptoms. LLS should be differentiated in a patient with gigantism without pituitary tumors. Although further investigation is necessary, this is the first study to suggest the involvement of aberrant GH signaling in the development of LLS.

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De novo 5q14.3 translocation 121.5-kb upstream of MEF2C in a patient with severe intellectual disability and early-onset epileptic encephalopathy

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.34289 ◽

2011 ◽

Vol 155 (11) ◽

pp. 2879-2884 ◽

Cited By ~ 15

Author(s):

Hirotomo Saitsu ◽

Noboru Igarashi ◽

Mitsuhiro Kato ◽

Ippei Okada ◽

Tomoki Kosho ◽

...

Keyword(s):

Intellectual Disability ◽

Early Onset ◽

De Novo ◽

Epileptic Encephalopathy ◽

Severe Intellectual Disability

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MYT1L mutation in a patient causes intellectual disability and early onset of obesity: a case report and review of the literature

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2018-0505 ◽

2019 ◽

Vol 32 (4) ◽

pp. 409-413 ◽

Cited By ~ 3

Author(s):

Abeer Al Tuwaijri ◽

Majid Alfadhel

Keyword(s):

Intellectual Disability ◽

Early Onset ◽

De Novo ◽

Copy Number Variants ◽

Speech Delay ◽

Single Nucleotide Variants ◽

Genome Wide ◽

Whole Exome ◽

Syndromic Obesity ◽

The Central Nervous System

Abstract Background Obesity has become one of the greatest health risks worldwide. Recently, there was an explosion of information regarding the role of the central nervous system (CNS) in the development of monogenic and syndromic obesity. Case presentation Over the last decade, terminal and interstitial submicroscopic deletions of copy number variants (CNVs) in 2p25.3 and single nucleotide variants (SNVs) in myelin transcription factor 1 like (MYT1L) were detected by genome-wide array analysis and whole exome sequencing (WES) in patients with a nonspecific clinical phenotype that commonly includes intellectual disability (ID), early onset of obesity and speech delay. Here, we report the first Saudi female patient with mild to moderate ID, early onset of obesity and speech delay associated with a de novo pathogenic SNV in the MYT1L gene (c. 1585G>A [Gly529Arg]), which causes an amino acid change from Gly to Arg at position 529 that leads to mental retardation, autosomal dominant 39.

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Early-onset central diabetes insipidus is associated with de novo arginine vasopressin–neurophysin II or Wolfram syndrome 1 gene mutations

Acta Endocrinologica ◽

10.1530/eje-14-0942 ◽

2015 ◽

Vol 172 (4) ◽

pp. 461-472 ◽

Cited By ~ 15

Author(s):

Silverio Perrotta ◽

Natascia Di Iorgi ◽

Fulvio Della Ragione ◽

Saverio Scianguetta ◽

Adriana Borriello ◽

...

Keyword(s):

Diabetes Insipidus ◽

Arginine Vasopressin ◽

Early Onset ◽

De Novo ◽

Novel Mutation ◽

Wolfram Syndrome ◽

Central Diabetes Insipidus ◽

Nucleotide Position ◽

Exon 2 ◽

Neurophysin Ii

ObjectiveIdiopathic early-onset central diabetes insipidus (CDI) might be due to mutations of arginine vasopressin–neurophysin II (AVP–NPII (AVP)) or wolframin (WFS1) genes.Design and methodsSequencing of AVP and WFS1 genes was performed in nine children with CDI, aged between 9 and 68 months, and negative family history for polyuria and polydipsia.ResultsTwo patients carried a mutation in the AVP gene: a heterozygous G-to-T transition at nucleotide position 322 of exon 2 (c.322G>T) resulting in a stop codon at position 108 (p.Glu108X), and a novel deletion from nucleotide 52 to 54 (c.52_54delTCC) producing a deletion of a serine at position 18 (p.Ser18del) of the AVP pre-prohormone signal peptide. A third patient carried two heterozygous mutations in the WFS1 gene localized on different alleles. The first change was A-to-G transition at nucleotide 997 in exon 8 (c.997A>G), resulting in a valine residue at position 333 in place of isoleucine (p.Ile333Val). The second novel mutation was a 3 bp insertion in exon 8, c.2392_2393insACG causing the addition of an aspartate residue at position 797 and the maintenance of the correct open reading frame (p. Asp797_Val798insAsp). While similar WFS1 protein levels were detected in fibroblasts from healthy subjects and from the patient and his parents, a major sensitivity to staurosporine-induced apoptosis was observed in the patient fibroblasts as well as in patients with Wolfram syndrome.ConclusionsEarly-onset CDI is associated with de novo mutations of the AVP gene and with hereditary WFS1 gene changes. These findings have valuable implications for management and genetic counseling.

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Abundant electrical myotonia and left ventricular noncompaction: Unusual features of Danon disease due to a novel mutation in LAMP2 gene

Revue Neurologique ◽

10.1016/j.neurol.2018.04.012 ◽

2019 ◽

Vol 175 (3) ◽

pp. 201-203 ◽

Cited By ~ 2

Author(s):

P. Codron ◽

V. Pautot ◽

A. Tassin ◽

D. Sternberg ◽

F. Letournel ◽

...

Keyword(s):

Novel Mutation ◽

Left Ventricular ◽

Left Ventricular Noncompaction ◽

Ventricular Noncompaction ◽

Danon Disease ◽

Lamp2 Gene

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Exome sequencing in a family with intellectual disability, early onset spasticity, and cerebellar atrophy detects a novel mutation in EXOSC3

Neurogenetics ◽

10.1007/s10048-013-0371-z ◽

2013 ◽

Vol 14 (3-4) ◽

pp. 247-250 ◽

Cited By ~ 27

Author(s):

Ginevra Zanni ◽

Chiara Scotton ◽

Chiara Passarelli ◽

Mingyan Fang ◽

Sabina Barresi ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Early Onset ◽

Novel Mutation ◽

Cerebellar Atrophy

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First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy

BMC Medical Genetics ◽

10.1186/s12881-015-0200-3 ◽

2015 ◽

Vol 16 (1) ◽

Cited By ~ 28

Author(s):

Katrien Smets ◽

Anna Duarri ◽

Tine Deconinck ◽

Berten Ceulemans ◽

Bart P. van de Warrenburg ◽

...

Keyword(s):

Intellectual Disability ◽

Cerebellar Ataxia ◽

Early Onset ◽

De Novo

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Pediatric leukemia susceptibility disorders: manifestations and management

Hematology ◽

10.1182/asheducation-2017.1.242 ◽

2017 ◽

Vol 2017 (1) ◽

pp. 242-250 ◽

Cited By ~ 6

Author(s):

Lisa J. McReynolds ◽

Sharon A. Savage

Keyword(s):

Early Onset ◽

Ribosome Biogenesis ◽

De Novo ◽

Disease Risk ◽

Bone Marrow Failure ◽

Clinical Manifestations ◽

Cancer Surveillance ◽

Therapeutic Interventions ◽

Pediatric Leukemia ◽

Inherited Susceptibility

Abstract The clinical manifestations of inherited susceptibility to leukemia encompass a wide phenotypic range, including patients with certain congenital anomalies or early-onset myelodysplastic syndrome (MDS) and some with no obvious medical problems until they develop leukemia. Leukemia susceptibility syndromes occur as a result of autosomal dominant, autosomal recessive, or X-linked recessive inheritance, or de novo occurrence, of germline pathogenic variants in DNA repair, ribosome biogenesis, telomere biology, hematopoietic transcription factors, tumor suppressors, and other critical cellular processes. Children and adults with cytopenias, MDS, dysmorphic features, notable infectious histories, immunodeficiency, certain dermatologic findings, lymphedema, unusual sensitivity to radiation or chemotherapy, or acute leukemia with a family history of early-onset cancer, pulmonary fibrosis, or alveolar proteinosis should be thoroughly evaluated for a leukemia susceptibility syndrome. Genetic testing and other diagnostic modalities have improved our ability to identify these patients and to counsel them and their family members for subsequent disease risk, cancer surveillance, and therapeutic interventions. Herein, the leukemia susceptibility syndromes are divided into 3 groups: (1) those associated with an underlying inherited bone marrow failure syndrome, (2) disorders in which MDS precedes leukemia development, and (3) those with a risk primarily of leukemia. Although children are the focus of this review, it is important for clinicians to recognize that inherited susceptibility to cancer can present at any age, even in older adults; genetic counseling is essential and prompt referral to experts in each syndrome is strongly recommended.

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