16p13.11 microduplication in 45 new patients: refined clinical significance and genotype–phenotype correlations

Abstract

BackgroundThe clinical significance of 16p13.11 duplications remains controversial while frequently detected in patients with developmental delay (DD), intellectual deficiency (ID) or autism spectrum disorder (ASD). Previously reported patients were not or poorly characterised. The absence of consensual recommendations leads to interpretation discrepancy and makes genetic counselling challenging. This study aims to decipher the genotype–phenotype correlations to improve genetic counselling and patients’ medical care.MethodsWe retrospectively analysed data from 16 013 patients referred to 12 genetic centers for DD, ID or ASD, and who had a chromosomal microarray analysis. The referring geneticists of patients for whom a 16p13.11 duplication was detected were asked to complete a questionnaire for detailed clinical and genetic data for the patients and their parents.ResultsClinical features are mainly speech delay and learning disabilities followed by ASD. A significant risk of cardiovascular disease was noted. About 90% of the patients inherited the duplication from a parent. At least one out of four parents carrying the duplication displayed a similar phenotype to the propositus. Genotype–phenotype correlations show no impact of the size of the duplicated segment on the severity of the phenotype. However, NDE1 and miR-484 seem to have an essential role in the neurocognitive phenotype.ConclusionOur study shows that 16p13.11 microduplications are likely pathogenic when detected in the context of DD/ID/ASD and supports an essential role of NDE1 and miR-484 in the neurocognitive phenotype. Moreover, it suggests the need for cardiac evaluation and follow-up and a large study to evaluate the aortic disease risk.

Clinical correlates in children with autism spectrum disorder and CNVs: Systematic investigation in a clinical setting

“…Patients bearing deletions within the 16p13.11 region have been reported to exhibit a spectrum of epilepsy disorders (Heinzen et al, 2010), microcephaly and developmental delay, in addition to psychiatric disorders (Nagamani et al, 2011). Inherited 16p13.11 microduplications are considered incompletely penetrant pathogenic mutations whose main clinical features are dysmorphic features, congenital anomalies, speech delay and learning disabilities followed by ASD (Allach et al, 2018). In all our three patients, 16p13.11 CNVs were inherited from the healthy father and encompassed the OMIM gene NDE1.…”

Submicroscopic aberrations of chromosome 16 in prenatal diagnosis

“…A total of 134 submicroscopic aberrations were identified in 117 (4.8%, 117/2,414) fetuses with normal karyotype or balanced structural aberration, including 51 cases of copy gain, 66 cases of copy loss, and 17 cases of loss of heterozygosity (LOH). Aberrations derived from chromosome 16,11.1% (15/134), were observed with the highest frequency, followed by those of chromosome 2 and 22 ( Fig. 1).…”

“…NDE1 (nudE nuclear distribution gene E homolog 1) and NTAN1 (N-terminal asparagine amidase) are the two genes that may be relevant to the neurocognitive phenotype. Loss or mutation of these genes has resulted in neurological manifestations in animal models, but the phenotypic consequences of gain are not that clear [10,11]. Microdeletions of 16p13.11 have been associated with multiple phenotypic manifestations, including neurodevelopmental phenotypes such as autism, epilepsy, and non-CNS phenotypes, such as physical dysmorphisms and other congenital anomalies [12][13][14][15].…”

“…Evidence has accumulated that 16p13.11 microduplication may be associated with autism, schizophrenia, epilepsy, and attention-deficit hyperactivity disorder [15][16][17]. However, both types of aberrations were also detected in individuals with normal phenotype [11,15]. This was interpreted by limited follow-up time.…”

Copy number alterations involving 59 ACMG‐recommended secondary findings genes

“…In addition, 0.38% of patients carry a duplication of the MYH11 gene, which appears to be a risk factor for aortic aneurysm and sudden death. 24,28 In at least two families, CMA results of the 33,34 Ordering clinicians and genetic counselors often view the results of microarray analysis as a set of the genes that are deleted or duplicated in their patients and examine each gene for its association with a known disease in the OMIM database. Unless a clear interpretation of the CNV for a specific gene is included in the laboratory report, this approach may lead to a misinterpretation of clinical significance.…”