ClinGen Dosage Sensitivity Curation Page

16p13.11 recurrent region (BP2-BP3) (includes MYH11)

  • Curation Status: Complete
  • id: ISCA-37415
  • Date last evaluated: 2016-04-14
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 2


Location Information

Select assembly: (NC_000016.9) ()
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
18550696 Hannes (2009) identified five patients with deletions of 16p13.11 covering 1.65 Mb, including 15 RefSeq genes, from a cohort of 1027 patients with intellectual disability and/or multiple congenital anomalies. Despite phenotypic variability, common features were identified: three patients presented with MR, microcephaly and epilepsy (two of these had also short stature), and two other deletion carriers ascertained prenatally presented with cleft lip and midline defects. No deletions were detected amongst 2014 reportedly normal controls, resulting in a p value of 0.0048. Some of these deletions were inherited from apparently unaffected family members. The authors noted that, while the deletion appeared significantly more often in the patient population than the controls, it showed incomplete penetrance.
19843651 de Kovel et al (2010) reported significant association of microdeletion 16p13.11 with epilepsy in a large case-control cohort and suggested that this deletion confer a pleiotropic susceptibility effect to a broad range of neuropsychiatric disorders (odds ratio = 7.4; 95% confidence interval 1.3?74.7; P = 0.009).
24246141 Jahn et al. (2014) screened 570 pediatric epilepsy cases for microdeletions 15q11.2, 15q13.3 and 16p13.11. They identified four patients with 16p13.11 deletions (0.7%). 16p13.11 microdeletions in their cohort were only found in patients with IGE or generalized EEG patterns and in one patient with West syndrome, but not in patients with focal epilepsies.

Haploinsufficiency phenotype comments:

Nagamani et al. (2011) proposed several different types of deletion/duplications with corresponding coordinates (PMID: 21150890) based upon the positioning of three single copy intervals between segmental duplications proposed by Ingason et al. (PMID:19786961). Interval I includes the genes RRN3 and PDXDC1 (chr16:15,000,000-15,300000); Interval II includes MYH11, NDE1 and ABCC6 (chr16:15,490,000- 16,300,000) and Interval III includes XYLT1 (chr16:17,000,000-18,250,000). Deletions and duplications most commonly include the genes in interval II but may extend to include intervals I and III. Tropeano et al. (2013) (PMID: 23637818) propose a "sex-limited effect on the penetrance of pathological phenotypes at the 16p13.11 locus;" they show that there was a significant enrichment of 16p13.11 deletions amongst male cases in their case-control sample set, but not amongst female cases (OR=infinity, P=0.001 for males, OR=1.16, P=1.00 for females). Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. In 2014, a Clinical Utility gene card for this microdeletion region was published (PMID:24105370). Candidate genes thought to be associated with the abnormal phenotype include NDE1 and NTAN1, although NTAN1 was not included in the critical deleted region (chr16: 15.48?16.32Mb, GRCh37/hg19).

  • Triplosensitivity score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for gain of function phenotype
PubMed ID Description
21614007 Ramalingam et al. (2011) evaluated 1645 pediatric patients using CGH and identified eight duplications in the 16p13.11 region. They reported variable phenotypes, with the most frequent being developmental delay and autistic spectrum disorder. Four of the eight were maternally inherited, and one was de novo.
23637818 Tropeano et al. (2013) observed duplications in 0.27% of a group of 10,397 individuals referred for clinical cytogenomic microarray testing, and in 0.12% of 11,277 controls (OR =2.15, P=0.019). They also noted significant enrichment in duplications amongst the male subgroup of the cases (OR=3.40, P=0.018), but not in the control subgroup (OR=1.21, P=0.708); the authors suggested a sex-biased effect on the penetrance of this CNV. Patients with the duplication presented with a variety of findings, including developmental delay and dysmorphic features, though the authors noted that 14/18 duplication patients over the age of 2 presented with a specific neurologic/neuropsychiatric phenotype, such as autism spectrum disorder, etc. Additionally, there has also been evidence to suggest that controls carrying CNVs associated with neurodevelopmental/neuropsychiatric conditions in cases may actually display some subtle cognitive effects.
24352232 Stefansson et al. (2014) performed cognitive testing on various "control" individuals carrying CNVs previously associated with autism or schizophrenia in patient populations. They determined that these carrier controls "perform at a level that is between that of schizophrenia patients and population controls." Specifically, carriers of the 16p13.1 duplication performed worse than population controls in areas of performance IQ (effect = 1.09, P = 9.30 x 10-6), verbal IQ (effect = 0.73, P=0.0022), and spatial working memory (effect =0.66, P=0.0049).

Triplosensitivity phenotype comment:

Several large-scale studies have shown no significant difference between the frequency of the duplications in cases versus controls: - Hannes et al. (2009) reported seven individuals with a duplication of 16p13.1 ascertained from a cohort of 1027 patients with intellectual disability and/or multiple congenital anomalies. The authors also detected this duplication in five control individuals from a cohort of 2014 reportedly normal individuals. From the article: "The incidence of duplications in association with disease is not significantly different from that in controls (p=0.1273). " Kaminsky et al. (2011): Identified 45 duplications among 15,749 individuals referred for clinical genetic testing, and 20 duplications among 10,118 published controls, for a P value of 0.203. The authors classified this duplication as a variant of uncertain significance (PMID: 21844811). Interestingly, Fujitani et al. (2016) showed that overexpression of miR-484 (within NDE1) resulted in a hyperactivity phenotype in a transgenic mouse model (PMID:2738146). Thus, although some authors support a causal role for the 16p13.11 duplication in abnormal neurodevelopmental phenotypes, others remain skeptical, due to the detection of the duplication in control populations. As a result, the clinical significance of these duplications is in doubt. Additional data is necessary to resolve these discrepancies.