Evaluation of 100 Dutch cases with 16p11.2 deletion and duplication syndromes; from clinical manifestations towards personalized treatment options

Abstract

The 16p11.2 deletion syndrome is a clinically heterogeneous disorder, characterized by developmental delay, intellectual disability, hyperphagia, obesity, macrocephaly and psychiatric problems. Cases with 16p11.2 duplication syndrome have similar neurodevelopmental problems, but typically show a partial 'mirror phenotype' with underweight and microcephaly. Various copy number variants (CNVs) of the chromosomal 16p11.2 region have been described. Most is known about the 'typical' 16p11.2 BP4-BP5 (29.6-30.2 Mb; ~600 kb) deletions and duplications, but there are also several published cohorts with more distal 16p11.2 BP2-BP3 CNVs (28.8-29.0 Mb; ~220 kb), who exhibit clinical overlap. We assessed 100 cases with various pathogenic 16p11.2 CNVs and compared their clinical characteristics to provide more clear genotype-phenotype correlations and raise awareness of the different 16p11.2 CNVs. Neurodevelopmental and weight issues were reported in the majority of cases. Cases with distal 16p11.2 BP2-BP3 deletion showed the most severe obesity phenotype (73.7% obesity, mean BMI SDS 3.2). In addition to the more well defined typical 16p11.2 BP4-BP5 and distal 16p11.2 BP2-BP3 CNVs, we describe the clinical features of five cases with other, overlapping, 16p11.2 CNVs in more detail. Interestingly, four cases had a second genetic diagnosis and 18 cases an additional gene variant of uncertain significance, that could potentially help explain the cases' phenotypes. In conclusion, we provide an overview of our Dutch cohort of cases with various pathogenic 16p11.2 CNVs and relevant second genetic findings, that can aid in adequately recognizing, diagnosing and counseling of individuals with 16p11.2 CNVs, and describe the personalized medicine for cases with these conditions.

Fig. 1. Overview of different 16p11.2 CNVs in our cohort.

This figure provides an overview of chromosome 16, including its short (p) and long (q) arms, as well as chromosomal bands and 16p11.2 breakpoints. A The recurrent typical ~600 kb 16p11.2 BP4-BP5 and distal ~220 kb 16p11.2 BP2-BP3 CNVs (deletions and duplications) are shown in more detail, including breakpoints (BPs) and genes in these regions. B The different 16p11.2 CNVs in our cohort, including the larger ‘other’ groups that are included in this study are shown, including the breakpoints.

Fig. 2. Frequencies of 16p11.2 CNV subtypes in our cohort.

Depicted are the different 16p11.2 CNVs identified in our cases, mainly consisting of typical 16p11.2 BP4-BP5 and distal 16p11.2 BP2-BP3 deletions (del) and duplications (dup), but also other (larger) deletions and duplications.

Fig. 3. Comparison of FSIQ and growth between 16p11.2 deletion and duplication subgroups.

Comparative boxplots representing General IQ, BMI SDS, OFC SDS, and height SDS across 16p11.2 deletion (red) and –duplication (blue) subgroups. Mean values for the deletion and duplication groups are illustrated with blue and red horizontal lines, respectively. A t test was performed to identify statistically significant differences between the deletion and duplication groups, * (p < 0.05), ** (p < 0.01), and *** (p < 0.001).