Sotos Syndrome via the NSD1 Gene

Sotos syndrome (OMIM 117550) is characterized clinically by cardinal features of craniofacial dysmorphism, childhood overgrowth, and learning disability. Variable features include behavioral problems; advanced bone age among childhood-aged patients; congenital heart defects; cranial defects; joint hyperlaxity; structural renal abnormalities; scoliosis; seizures; and jaundice, poor feeding, and hypotonia in newborns (Cole, Tatton-Brown and Rahman. GeneReviews, 2009). Children with Sotos syndrome uniformly have macrocephaly, approximately half of which is acquired in the first year of life. Other craniofacial features include dolicocephaly, sparse hair in the frontopareital region, prominent jaw, down-slanting palpebral fissures, and malar flushing. Mental deficiency is variable ranging from mild to severe. Early signs of delay are apparent and often motor delay is first noticeable because of poor coordination and hypotonia. Overgrowth is prenatal in onset, and length is affected more than weight. Through childhood and adolescence growth remains at or above 97th percentile, but final height is often within normal range. An estimated risk of 3.9% for developing benign or malignant tumors has been proposed for Sotos syndrome (Gorlin et al. Syndromes of the Head and Neck. 3rd Ed. NY, Oxford Univ Press, 1990).

Sotos syndrome is a fully penetrant autosomal dominant disorder. Approximately 95% of Sotos syndrome patients have de novo NSD1 variants, and 5% have an affected parent. Haploinsufficiency for NSD1, the most common etiology, results from intragenic point variants (~80%), 5q35 microdeletions (~10%) or partial NSD1 gene deletions (~5%), (Douglas et al. Am J Hum Genet 72:132-143, 2003; Tatton-Brown et al. Am J Hum Genet 77:193-204, 2005). Missense variants are limited to functional domains of the protein while nonsense variants occur throughout the protein. Compared to patients with NSD1 intragenic point variants, patients with microdeletions have been found to have more severe learning disability and less prominent overgrowth (Tatton-Brown et al. 2005). Some patients with Weaver syndrome (OMIM 277590) have been found to also have variants in the NSD1 gene (Douglas et al. 2003).

Clinical sensitivity of NSD1 sequencing should be high in children with the facial gestalt in conjunction with overgrowth, macrocephaly, and developmental delay (Turkmen at al. Europ J Hum Genet 11:858-865, 2003). Among 266 NSD1 positive patients, Tatton-Brown et al. (2005) found point variants in 83%. Similarly, Douglas et al. (2003) found NSD1 point variants in 76% of a group of subjects characterized as typical Sotos syndrome patients. The same authors found three of seven Weaver syndrome patients to have NSD1 variants, all between amino acids 2142 and 2184.

This test provides full coverage of all coding exons of the NSD1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).