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This has allowed better identification and classification of cases with previously uncategorised phenotypic clusters, as new gene variants are progressively discovered and classified. In the case of non-syndromic intellectual disability, the current use of next-generation sequencing techniques has allowed the identification of multiple associated gene mutations,<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> even in adulthood, as in the case described here.</p><p id="par0010" class="elsevierStylePara elsevierViewall">We report the case of a 35-year-old woman with multiple phenotypic alterations (intellectual disability, delayed speech development, facial dysmorphia, generalised hypotonia, clinodactyly, and behavioural and sleep disorders) of unknown aetiology, who was requested to undergo a phenotype-driven exome sequencing analysis, finding a pathogenic homozygous variant in gene <span class="elsevierStyleItalic">NDST1</span> associated with autosomal recessive intellectual disability type 46.</p><p id="par0015" class="elsevierStylePara elsevierViewall">35-year-old woman, with a family history of type 2 diabetes mellitus in parents and a personal history of intellectual disability and delayed psychomotor development, referred for phenotype assessment. She was on oxcarbamazepine 300 mg/5 ml 10 ml/12 h, clonazepam 2.50 mg/mL 5 drops/8 h and olanzapine 5 mg/24 h prescribed by Mental Health for behavioural problems. Non-consanguineous parents. History-taking revealed behavioural disorders since childhood, with a prevalence of aggressiveness and agitation, as well as delayed speech development, stereotypies and insomnia. Sporadic episodes of loss of muscle tone and falls, without loss of consciousness, lasting seconds, with restitutio ad integrum. No history of seizures.</p><p id="par0020" class="elsevierStylePara elsevierViewall">On physical examination, vital signs were normal. There was no evidence of orthostatic hypotension. She had generalised hypotonia with proximal predominance, bilateral clinodactyly, cervical kyphosis and dorsolumbar scoliosis (positive Adams test). Craniofacial features included hypertelorism, low-set ears and dental crowding. Stereotyped movements in the right upper limb. Bilateral genu valgum and flat feet were evident in the lower limbs.</p><p id="par0025" class="elsevierStylePara elsevierViewall">As part of the study, laboratory determinations were made without hormonal, biochemical or haemometric changes. Cranial magnetic resonance imaging showed no abnormalities. The study of the episodes of loss of muscle tone was completed with electrocardiogram, transthoracic echocardiography, Doppler ultrasound of the supra-aortic trunks and electroencephalogram, all of which were normal.</p><p id="par0030" class="elsevierStylePara elsevierViewall">A phenotype-driven exome analysis using NGS (next-generation sequencing) revealed a pathogenic homozygous variant c.1831 G > A (p.G611S) in the NDST1 gene, confirming the diagnosis of autosomal recessive intellectual disability type 46.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Intellectual disability is a common clinical entity with a prevalence of 1–3 % in the population,<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> classically divided into syndromic and non-syndromic. It has a very broad phenotypic spectrum of varying severity and is a genetically heterogeneous entity, with more than a thousand associated genes described thanks to the advent of next-generation sequencing.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> One of the most recent associations is gene NDST1 (N-Deacetylase, N-sulfotransferase 1).</p><p id="par0040" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">NDST1</span>gene, located on chromosome 5q33, encodes one of the enzymes of the heparan sulphate synthesis pathway, which is highly expressed in brain tissue and is involved in synaptic plasticity and embryonic development. The pathogenic variant described results in loss of N-sulfotransferase activity with preservation of N-deacetylase activity. The direct consequence is the loss of N-sulfation of <span class="elsevierStyleItalic">NDST1</span>, which has been associated with cognitive function impairment.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Pathogenic variants of this gene have been associated with a condition called autosomal recessive intellectual disability type 46 (OMIM#616116).<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In addition to intellectual impairment, growth retardation, hypotonia, neurological impairment (delayed psychomotor development, speech impairment and epilepsy), behavioural disturbances (agitation, aggressiveness), sleep disturbances and facial dysmorphic disorders have been reported.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> To date, there are few cases of this entity described in the literature.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,4</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">We highlight the importance of the application of phenotype-driven whole exome sequencing techniques for the diagnosis and classification of clinical conditions with phenotypic clustering of unknown aetiology, as in the case of intellectual disability, thus enabling better care and management.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Ethical considerations</span><p id="par0055" class="elsevierStylePara elsevierViewall">Informed consent was obtained for subsequent publication.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Funding</span><p id="par0060" class="elsevierStylePara elsevierViewall">Not funded.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Conflict of interest</span><p id="par0065" class="elsevierStylePara elsevierViewall">No conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Ethical considerations" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Funding" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Conflict of interest" ] 3 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Next-generation sequencing in unexplained intellectual disability" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. 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Journal Information
Vol. 163. Issue 6.
Pages 309-310 (September 2024)
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Vol. 163. Issue 6.
Pages 309-310 (September 2024)
Letter to the Editor
Identification of NDST1 variant as a cause of intellectual disability
Identificación de variante en NDST1 como causa de discapacidad intelectual
Antonio Rosales-Castillo
, Antonio Bustos-Merlo, Joaquín Escobar Sevilla
Corresponding author
Servicio de Medicina Interna, Hospital Universitario Virgen de las Nieves, Granada, Spain
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