ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000003.11) (NC_000003.12)
Evidence for haploinsufficiency 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.

Haploinsufficiency phenotype comments:

Additional publication (PMID 23160955) O'Roak et al (2012): Candidate gene study of 2446 ASD probands from the Simons Simplex Collection: 1 autism female with de novo frameshift SETD2 mutation (chr3:47098932, p.Asn2114IlefsX33). 1 autism male with de novo missense SETD2 mutation (chr3:47166005, p.Ile41Phe). 2 autism males with inherited nonsense SETD2 mutations (chr3:47205396, p.Gln7X; chr3:47164944, p.Cys394X) ------ gnomAD: 29 LOF ExAC pLI: 1.00 The evidence for LOF mutations of SETD2 resulting in Luscan-Lumish syndrome (macrocephaly, intellectual disability, speech delay, low sociability, and behavioral problems) doesn't appear to be conclusive: - The overgrowth/macrocephaly phenotype doesn't segregate with the SETD2 mutations in Tlemsani et al. - The 29 individuals with LOF mutations in gnomAD are unlikely to all have Luscan-Lumish syndrome. - 2 autism patients with inherited SETD LOF mutations. - However, pLI = 1. Overall -> haploinsufficiency score of 2 for Luscan-Lumish syndrome due to the presence of LOF mutations in people without this syndrome. SETD2 could however be associated with a more generalised neurodevelopmental phenotype.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

No evidence found.