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NSD1

Alias

ARA267; KMT3B; SOTOS; SOTOS1; STO

Associated disorders

The NSD1 gene is associated with autosomal dominant Sotos syndrome (MedGen UID: 833601).

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NSD1

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The NSD1 gene encodes a histone methyltransferase with multiple functional domains. Histones are proteins bound to DNA that give structure to chromosomes. The placement of histones allows for genes to be actively transcribed or turned off. The NSD1 protein functions to add methyl groups to histones, subsequently controlling the transcription of the surrounding genes. Proper functioning of this process is essential for normal growth and development (PMID: 21196496, 9628876, 24412544).

NSD1

Clinical condition

NSD1 is associated with Sotos syndrome, which belongs to a group of overgrowth disorders. Three main characteristic features of the syndrome include: distinctive facial features (prominent forehead, downslanting palpebral fissures, long, narrow facies with pointed chin), learning disability, and overgrowth with advanced bone age. Both head size and height over two standard deviations above the mean in childhood are prominent features. Macrocephaly remains throughout the life span but height normalizes with age. Affected individuals often have intellectual disability and behavioral problems (PMID:15942875). Other features of Sotos syndrome include: scoliosis, seizures, cardiac (20% of cases) and renal anomalies (15% of cases), and neonatal hypotonia (PMID: 20301652).

Ventricular dilatation is a frequent cranial MRI/CT finding (PMID: 16247291). There is evidence of an increased risk for certain tumors (PMID:15942875) with the risk for affected individuals to develop cancer only slightly above the population risk (Genetics Home Reference. NSD1. https://ghr.nlm.nih.gov/gene/NSD1. Accessed April 2017). No tumor or cancer surveillance is recommended.

Differential diagnosis
Other overgrowth syndromes include: Beckwith-Wiedemann syndrome, Perlman syndrome, Weaver syndrome, Neurofibromatosis 1, Legius, Marshall-Smith, Simpson-Golabi-Behmel, Pallister-Hall and PTEN-related syndromes.

Gene information
The NSD1 gene encodes a histone methyltransferase with multiple functional domains. Histones are proteins bound to DNA that give structure to chromosomes. The placement of histones allows for genes to be actively transcribed or turned off. The NSD1 protein functions to add methyl groups to histones, subsequently controlling the transcription of the surrounding genes. Proper functioning of this process is essential for normal growth and development (PMID: 21196496, 9628876, 24412544).

Changes in the NSD1 gene have been associated with cancer. The fusion between the NSD1 gene and the NUP98 gene leads to the development of acute myeloid leukemia. Another alteration in the NSD1 gene is associated neuroblastoma and glioma. Absence of NSD1 may lead to uncontrolled cell growth leading to cancer (Genetics Home Reference. NSD1. https://ghr.nlm.nih.gov/gene/NSD1. Accessed April 2017).

Inheritance
NSD1 shows autosomal dominant inheritance.

Penetrance
NSD1 is thought to be fully penetrant but shows a high degree of variable expression (PMID: 15942875).

Management
At the time of diagnosis, echocardiogram, hearing evaluation, and renal ultrasound are recommended. Ventricular dilatation, which is often noted on MRI in Sotos patients, does not usually necessitate shunting. If intracranial pressure is noted, appropriate referral to neurology and neurosurgery is warranted (PMID: 16969376).

In a literature review of adult Sotos patients, the most common features requiring monitoring included: learning disabilities, scoliosis, visual problems, psychiatric issues, and brain imaging anomalies (PMID: 21834047).

Referral to clinical genetics for surveillance and genetic counseling is recommended.

Review date: April 2017

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
NSD1 NM_022455.4