Balkan Journal of Medical Genetics

DUPLICATION OF CHROMOSOME 16p13.11-p12.3 WITH DIFFERENT EXPRESSIONS IN THE SAME FAMILY
Pop-Jordanova N1,*, Zorcec T2, Sukarova-Angelovska E2, 3
*Corresponding Author: Professor Nadica Pop-Jardonica, Department of Medicine, Research Centre for Genetic Engineering and Biotechnology “Georgi D. Efremov,” Macedonian Academy of Sciences and Arts, Bul. Krste Misirkov 2, 1000 Skopje, Republic of North Macedonia. Tel.: +389-2-32-35-400. Fax: +389-2-32-35-423. E-mail: popjordanova.nadica@gmail.com
page: 89

DISCUSSION

Generalized clinical use of chromosomal microarray analysis (CMA) in etiological investigation of neurodevelopmental disorders, has led to the decryption of many new CNVs, such as those in 16p13.11. Structural variation of the human genome results from genomic rearrangements including deletions, duplications, insertions and inversions. All of these genomic rearrangements, except for inversions, result in CNV or deviation from the normal number of copies for a given genomic segment. Although the widespread utilization of one such tool, aCGH has led to the discovery of many novel genomic disorders. One such CNV with a yet uncharacterized clinical phenotype is a rearrangement in chromosome 16p13.11, associated with epilepsy, multiple congenital anomalies and cognitive impairment, while duplications have been implicated in ASDs, intellectual disability and schizophrenia [9,10]. The Medical Genetics Laboratories at Baylor College of Medicine, Houston, TX, USA has performed over 14,000 aCGH for clinical evaluation of subjects with DD, dysmorphic features and/or multiple congenital anomalies from June 2007 to January 2010 [6]. During this period, they identified 56 patients with duplications and 30 patients with deletions of 16p13.11. Nagamani et al. [6] concluded that the clinical spectrum associated with both duplications and deletions are quite variable and the manifestations are incompletely penetrant, making genetic counseling of such families a challenging prospect. Ramalingam et al. [11] confirmed that the clinical significance of 16p13.11 duplications remains controversial, while frequently detected in patients with DD, intellectual deficiency (ID) or ASD. Searching in the literature, we found a study by Ullmann et al. [12], who described a 1.5 Mb duplication on chromosome 16p13.1 that was found by high resolution aCGH in four severe autistic male patients from three unrelated families. In a study by Tropeano et al. [13], there was reported evidence for a male-biased autosomal effect of 16p13.11 duplications and deletions in a sample of 10,397 individuals with a neurodevelopmental condition, analyzed by whole genome aCGH. The CNVs identified included 28 duplications with sizes ranging from 0.8 to 3.29 Mb, and 18 deletions with sizes between 0.02 and 3.26 Mb [two non allelic homologous recombination (NAHR)- mediated]. It was suggested that CNVs at chromosome 16p13.11 have been associated with a range of neurodevelopmental disorders including autism, attention deficit hyperactivity disorder (ADHD) intellectual disability and schizophrenia [14]. Quintela et al. [14] described maternally inherited 16p13.11-p12.3 duplication and a de novo 12p12.1 deletion affecting SOX5 in a male patient with global DD, disruptive and obsessive behaviors and minor dysmorphic features. It was noted that the 16p13.11 micro duplication has been implicated in several neurodevelopmental and behavioral disorders and is characterized by variable expressivity and incomplete penetrance [14]. In this context, Pinto et al. [15] published exome sequencing analysis in a pair of monozygotic twins that reevaluates the genetics behind their intellectual disability and reveals a CHD2 mutation in two monozygotic twins. An aCGH analysis revealed two maternally inherited duplications on chromosomes 8p22 and 16p13.11 in both twins. Their study underlines the importance of considering a CHD2 gene involvement in children with intellectual disability and ASD [15]. Srivastava et al. [16] suggested the high diagnostic yield of WES and supported its use in pediatric neurology practices. This method may also lead to earlier diagnosis, impacting medical management, prognostication and family planning. Therefore, WES serves as a critical tool for the child neurologist [16]. Unlike apparent CNV that are clearly pathogenic, 16p micro duplication have a wide range of phenotypic variability. Intra familial phenotypic variability of 16p11.2 duplication syndrome has been described in many reports, ranging from normal to severely affected cognitive impairment [17,18]. Our finding is similar to those described in the literature, having unaffected father and the latter two children, and variable presentation of autism in the first two children. The reason for such variability could be the existence of a recessive mutation in one of the genes on the maternal chromosome, existence of an imprinted gene in the region, or involvement of other modifier genes that contribute the phenotype. Conclusions. Our case report confirmed the genetic involvement of arr cgh 16p.13.11 in neurodevelopmental delay combined with autistic behavior in two siblings and the father in the same family. The obtained results are supported in some other studies. The same gene mutation was found in twin brothers, with no significant developmental issues so far. The clinical spectrum associated with both duplications and deletions are quite variable and the manifestations are incompletely penetrant, making genetic counseling of such families difficult. However, genetic evaluation in the large spectrum of neurodevelopmental disorders is needed. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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