ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

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Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
24852293 Luscan et al (2014): Targeted NGS of 22 methylation-related genes in 16 patients (Sotos, Sotos-like and Weaver syndrome). Nonsense SETD2 p.Gln274* mutation in an adopted, 7yr old girl referred for speech delay, overgrowth and overweight. Weight 75?kg (>97th centile). BMI 23. Height 137?cm (>97th centile). OFC was 57?cm (>97th centile). Prominent forehead with high frontal hairline. Downward slanting palpebral fissures. Prominent mandible. Long and large hands and feet. Frequent ear and renal infections without any associated malformations. CT scan showed mild ventricular dilatation. Full-scale IQ score 91, with verbal IQ 99 and performance IQ 80. Ophthalmological evaluation, EEG, metabolic screen in blood and urine, endocrinologic screen were all normal. Also one de novo missense in paper.
26084711 Lumish et al (2015): WES trio (Sureselect all exon v4). De novo frameshift SETD2 c.2028delT (P677LfsX19) mutation in a 17yr old girl referred for ASD, developmental delay, ID, seizures, Chiari I malformation, macrocephaly, and short stature. Birth weight 3.8 kg (90th percentile). Birth length of 48.3 cm (25th?50th percentile). Prenatal ultrasound showed choroid plexus cysts. Neonatal course was notable for weak suck, hypotonia, and nearly continuous sleeping, except when she was awakened to feed. Weight declined to the 20th percentile by 6 months. At 17 yrs: Height 5th percentile. Macrocephalic (head circumference >97th percentile) since 6 months of age. Developmentally delayed. Did not walk until 18 months of age. Did not begin speaking until 2 years of age. Fine and gross motor skills delays. Expressive and receptive language delays. First seizure occurred at 10 years of age (generalized tonic?clonic). Docile and cheerful as a young child, then became increasingly aggressive. Clinical diagnosis of an anxiety disorder, attention deficit hyperactivity disorder, and ASD at 7 years of age.
27317772 Tlemsani et al (2016): Targeted NGS of DNMT3A & SETD2 in 210 NSD1 mutation negative, Sotos-like patients. De novo frameshift SETD2 c.5285_5286 delAC (p.His1762Leufs*26) mutation in a 12yr old boy referred for ID, tall stature, macrocephaly, dysmorphy, caf?-au-lait spots and hyperchromic spots following the lines of Blaschko. Neonatal hypotonia. Feedings difficulties in the first months. Psychomotor retardation (able to walk at 21?months, first words at 3?years). At 12 yrs: Able to speak complete sentences but did not have meaningful communication. Younger sister without the SETD2 mutation but with tall stature (+2 SD), macrocephaly (+2.3 SD) and Blaschkoid skin spots on arms. No hypotonia at birth and was able to walk at 15?months. Able to speak with sentences at 3?years. Mild learning difficulties but no ID (IQ 95). Not dysmorphic.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.