
==== Front
Hum Genomics
Hum Genomics
Human Genomics
1473-9542
1479-7364
BioMed Central London

39232803
662
10.1186/s40246-024-00662-0
Research
Chromosome 16p11.2 microdeletion syndrome with microcephaly and Dandy-Walker malformation spectrum: expanding the known phenotype
Elsayed Liena Elbaghir Omer 1
AlHarbi Norah Ayed Noaalharbi@pnu.edu.sa

2
Alqarni Ashwaq Mohammed 3
Eltayeb Huda Hussein Elwasila 1
Mostafa Noura Mostafa Mohamed 14
Abdulrahim Maha Mohammed 5
Zaid Hadeel Ibrahim Bin 6
Alanzi Latifah Mansour 7
Ababtain Sarah Abdullah 8
Aldulaijan Khawlah 8
Aloyouni Sheka Yagub 8
Othman Moneeb Abdullah Kassem 9
Alkheilewi Mohammad Abdullah 10
Binduraihem Adel Mohammed 8
Alrukban Hadeel Abdollah 11
Ahmed Hiba Yousif 12
AlRadini Faten Abdullah 15
Alahdal Hadil Mohammad 13
Mushiba Aziza Mufareh 1214
Alzaher Omaima Abdulazeem 16
1 https://ror.org/05b0cyh02 grid.449346.8 0000 0004 0501 7602 Department of Basic Sciences, College of Medicine, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh, 11671 Saudi Arabia
2 https://ror.org/05b0cyh02 grid.449346.8 0000 0004 0501 7602 Department of Internal Medicine, College of Medicine, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh, 11671 Saudi Arabia
3 https://ror.org/05b0cyh02 grid.449346.8 0000 0004 0501 7602 Foundation Year of Health Colleges, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
4 https://ror.org/053g6we49 grid.31451.32 0000 0001 2158 2757 Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
5 grid.449346.8 0000 0004 0501 7602 Research and Academic Accreditation, Academic Affairs, King Abdullah bin Abdulaziz University Hospital, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh, 11671 Saudi Arabia
6 grid.449346.8 0000 0004 0501 7602 Out-Patient department, King Abdullah bin Abdulaziz University Hospital, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
7 grid.449346.8 0000 0004 0501 7602 Department of Pathology and Laboratory Medicine, King Abdullah Bin Abdulaziz University Hospital, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
8 https://ror.org/05b0cyh02 grid.449346.8 0000 0004 0501 7602 Genetics Section, Research Department, Health Sciences Research Center, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh, 11671 Saudi Arabia
9 grid.511058.8 0000 0004 0548 4972 Centogene GmbH, Rostock, Germany
10 grid.415696.9 0000 0004 0573 9824 Health Support Services Centre, Ministry of Health, Riyadh, 12382 Saudi Arabia
11 https://ror.org/00mtny680 grid.415989.8 0000 0000 9759 8141 Pediatric Department, Division of Genetic and Metabolic, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
12 grid.449346.8 0000 0004 0501 7602 Pediatrics department, King Abdullah bin Abdulaziz University Hospital, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
13 https://ror.org/05b0cyh02 grid.449346.8 0000 0004 0501 7602 Department of Biology, College of Science, Princes Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh, 11671 Saudi Arabia
14 https://ror.org/01jgj2p89 grid.415277.2 0000 0004 0593 1832 Section of Medical Genetics, Children’s Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
15 https://ror.org/05b0cyh02 grid.449346.8 0000 0004 0501 7602 Family and Community Medicine Department, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
16 https://ror.org/05b0cyh02 grid.449346.8 0000 0004 0501 7602 Pediatric Department, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
4 9 2024
4 9 2024
2024
18 9520 12 2023
19 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Background

Chromosome 16p11.2 deletions and duplications were found to be the second most common copy number variation (CNV) reported in cases with clinical presentation suggestive of chromosomal syndromes. Chromosome 16p11.2 deletion syndrome shows remarkable phenotypic heterogeneity with a wide variability of presentation extending from normal development and cognition to severe phenotypes. The clinical spectrum ranges from neurocognitive and global developmental delay (GDD), intellectual disability, and language defects (dysarthria /apraxia) to neuropsychiatric and autism spectrum disorders. Other presentations include dysmorphic features, congenital malformations, insulin resistance, and a tendency for obesity. Our study aims to narrow the gap of knowledge in Saudi Arabia and the Middle Eastern and Northern African (MENA) region about genetic disorders, particularly CNV-associated disorders. Despite their rarity, genetic studies in the MENA region revealed high potential with remarkable genetic and phenotypic novelty.

Results

We identified a heterozygous de novo recurrent proximal chromosome 16p11.2 microdeletion by microarray (arr[GRCh38]16p11.2(29555974_30166595)x1) [(arr[GRCh37]16p11.2(29567295_30177916)x1)] and confirmed by whole exome sequencing (arr[GRCh37]16p11.2(29635211_30199850)x1). We report a Saudi girl with severe motor and cognitive disability, myoclonic epilepsy, deafness, and visual impairment carrying the above-described deletion. Our study broadens the known phenotypic spectrum associated with recurrent proximal 16p11.2 microdeletion syndrome to include developmental dysplasia of the hip, optic atrophy, and a flat retina. Notably, the patient exhibited a rare combination of microcephaly, features consistent with the Dandy-Walker spectrum, and a thin corpus callosum (TCC), which are extremely infrequent presentations in patients with the 16p11.2 microdeletion. Additionally, the patient displayed areas of skin and hair hypopigmentation, attributed to a homozygous hypomorphic allele in the TYR gene.

Conclusion

This report expands on the clinical phenotype associated with proximal 16p11.2 microdeletion syndrome, highlighting the potential of genetic research in Saudi Arabia and the MENA region. It underscores the importance of similar future studies.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40246-024-00662-0.

Keywords

de novo
Recurrent proximal chromosome 16p11.2 microdeletion syndrome
Saudi Arabia
Global developmental delay
Cognitive impairment
Optic atrophy
Microcephaly
Myoclonic epilepsy
Dandy-walker spectrum
This research was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University, through the Research Funding ProgramGrant No. (FRP-1443-5 issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcBackground

Copy Number Variations (CNVs) are structural variations defined as deletions/duplications of 50 base pairs or more [1]. They are considered a relatively common cause of human disease especially involved in the pathogenesis of developmental disabilities [2]. Large pathogenic CNVs have been linked to various phenotypic alterations in recent large population-based cohorts [1, 3]. [2]. CNVs associated with neurodevelopmental delay (NDD CNVs) were reported to occur in around 1 in 200 newborns (prevalence of 0.48%), with a third of these being de novo CNVs [4]. CNVs in the 16p11.2 region were linked to five rare disorders: 16p11.2p12.2 microdeletion [ORPHA:261211]/microduplication [ORPHA:261204], proximal and distal 16p11.2 microdeletion [ORPHA:261197 and ORPHA:261222], and proximal 16p11.2 microduplication syndromes [ORPHA:370079] [5, 6]. Chromosome 16p11.2 rearrangements (deletions/duplications) were found to be the second most commonly reported CNVs in cases with clinical features suggestive of chromosomal syndromes, with a frequency of 1 in 235 for the deletions and 1 in 404 for the duplications [2]. Overall, low expressivity and incomplete penetrance were observed in chromosome 16p11.2 deletions and duplications [7].

There are variations in the size and location of the deleted genomic region involved in the etiology of 16p11.2 microdeletion syndrome (OMIM #611913). However, deletions affecting the proximal 16p11.2 region are classically defined as a recurrent ~ 600 kb CNV between breakpoints (BP4 and BP5)] encompassing up to around 29 protein-coding genes [8, 9]. The syndrome has an incidence of around 1/2000 [10] with an estimated prevalence of 1–5/10,000 in the general population, whereas different studies reported a prevalence of 1.5% in cases of developmental or language delay, 1% of ASD, and 0.001% of cases presenting with psychiatric disorders [7, 10–13]. 75% of the cases were reported to occur de novo with only 7% being inherited [10, 12]. Phenotypically, it shows remarkable heterogeneity with extreme variability of presentation in line with its reported pleiotropy and the large number of phenotypic traits associated with it (mounting to 26) in numerous studies [3, 14, 15]. The presentation of patients with the 16p11.2- BP4-BP5 deletion syndrome ranges from normal development and cognition to severe phenotypes. Recent studies have provided compelling evidence of the pleiotropic effects associated with recurrent CNVs with 16p11.2 The spectrum of clinical manifestations associated with it spans neurocognitive delay, intellectual disability (ID), language impairment (dysarthria /apraxia), neuropsychiatric disorders, autism spectrum disorders (ASD), global developmental delay (GDD), dysmorphic features, congenital malformations, tendency for obesity, and more [7, 10, 13].

There is a notable scarcity of genetic studies in the Middle East and North Africa (MENA) region, especially of research on CNV-associated disorders and their impact on health, despite the demonstrated high potential of novel discoveries in this region that is attributed to the richness and novelty of genetic and phenotypic data. Our study aimed at expanding the knowledge about the genetic disorders in the MENA region and Saudi Arabia predicting a remarkable impact, not only locally and regionally, but also internationally. In this report, we expand the phenotypes associated with recurrent proximal chromosome 16p11.2 microdeletion syndrome, reporting a complex neurological phenotype in a Saudi girl that was associated with novel neurological features and areas of abnormal skin and hair pigmentation attributed to a concurrent homozygous hypomorphic allele in the TYR gene.

Method

Phenotyping

The patient and the two parents were phenotyped by the referring neuro-pediatrician and the clinical geneticist. A second standardized detailed phenotyping of the patient and the two parents was done by the research team. Specialized ophthalmological, auditory, cardiac, and orthopedic assessments were performed, and the patient’s medical records were reviewed. The radiological assessments of the patient that were performed included magnetic resonance imaging (MRI) of the brain, X-rays, and echocardiography. All necessary laboratory and neurophysiological investigations were also performed.

Genetics

DNA was extracted from blood using specialized DNA extraction kits according to the manufacturer’s protocol (kit name, company, etc.).

Microarray

Genomic DNA was fragmented, amplified, and hybridized to the array according to the manufacturer’s manual. Cytoscan HD array Affymetrix® which contained 2.7 million markers including 750,000 SNP markers was used. It enabled the detection of CNVs and/or large duplications /deletions. The chromosome analysis suite (ChAS Affymetrix) was used to analyze the results with CNVs larger than the size threshold of more than 200Kbs (for duplications) and 50Kbs (for deletions) reported. Although the choice of the cut-off sizes is usually influenced by the sensitivity and the specificity of the microarray platform, these sizes strike a balance between resolution, clinical relevance, and technological constraints, making them commonly used and effective thresholds for aCGH analysis in clinical and research settings [16–19].

Additionally, analysis was performed for all homozygous deletions which included aberrations of at least five aberrant markers (1Kb in size). Identified deletions below the above-given thresholds were only reported when a clear phenotypic overlap of affected genes was observed. Analysis was done based on the human genome assembly GRCh38 according to the preset pipeline, however, the GRCh37-based genomic positions were also identified using the University of California Santa Cruz (UCSC) Genomic Institute genome browser tool (LiftOver). Database of Genomic Variants (DGV) and Decipher database in addition to other available databases were used in result interpretation.

Whole exome sequencing (WES)

WES was performed on the patient and the two healthy parents (Trio WES). DNA was fragmented enzymatically. Target region enrichment was done using DNA capture probes. It included the human exome (the coding exons and the flanking -/+ 10 bases of the intronic regions of genes) covering more than 98% of the RefSeq coding sequence [human genome built GRCh37/hg19]) in addition to the mitochondrial genome. The generated library was sequenced via the Illumina platform and 20X depth was achieved for more than 98% of the targeted bases. The bioinformatics pipeline used for analysis included alignment with GRCh37/hg19 human genome assembly and revised Cambridge Reference Sequence of the mitochondrial DNA (NC_012920), followed by variant calling, annotation, and filtering [20]. All potential modes of inheritance were considered with all variants with a minor allele frequency of less than 1% in gnomAD v2.1 database and disease-causing variants reported in HGMD® Professional 2022.1, ClinVar, or in CentoMD® were evaluated. Variants were classified into five categories (pathogenic, likely pathogenic, variants of uncertain significance (VUS), likely benign, benign) along American College of Medical Genetics (ACMG) guidelines. Relevant variants related to the phenotype were reported and analyzed by PCR and sequencing of both strands of the entire coding region and the highly conserved exon-intron splice junctions.

We used an in-house pipeline for the detection of CNVs with a specific algorithm for the identification of uniparental disomy (UPD) screening. It includes the identification of the ROH in WES data via an H3M2-based algorithm, which uses the pileup format (https://en.wikipedia.org/wiki/Pileup_format) generated from BAM files [21] A CNV caller DECoN (Detection of Exon Copy Number) was used. It is specifically designed for targeted sequencing data and employs a Bayesian approach to distinguish biological differences from technical noise for each target region [22]. We annotate and rank structural variations (SV) using the tool AnnotSV [23].

Results

Clinical presentation

We present a 22-month-old Saudi girl with significant GDD, bilateral developmental dislocation and dysplasia of the hip more on the left side, myoclonic generalized epilepsy, impaired hearing, poor vision, and cutaneous hypopigmentation. She was the only child of healthy consanguineous parents in a family (PNU-NG3) with multiple consanguinity loops over generations originating from the south of Saudi Arabia. The patient’s remarkable GDD was evidenced by her inability to accomplish the majority of the milestones that were expected at her age. She had limited recognition of her parents, poor visual fixation, and minimal interaction with her surroundings. She was capable of producing some non-comprehensive sounds and could roll from supine to prone positions but was unable to sit, even with support.

The myoclonic seizures were first observed by the neuro-pediatrician during consultation at the age of seven months. An electroencephalogram (EEG) confirmed generalized epileptic activity consistent with the diagnosis of myoclonic epilepsy and the patient was started on Levetiracetam as antiseizure medication. Although clinical seizures were controlled, follow-up EEGs showed the persistence of less frequent epileptic discharges.

At 22 months, clinical examination revealed microcephaly with a head circumference of 37 cm, failure to thrive with a weight of 6.3 kg, and short stature with a length of 72 cm. All her growth parameters were far below the third percentile for age and sex. The patient displayed plaques and macules of hypopigmentation on her face and extremities, along with streaks of white hair and white eyelashes. The hypopigmentation appeared to progress slowly. Dysmorphic features included low-set ears, retracted forehead and chin, prominent maxillae and occiput, and high-arched palate were detected (Fig. 1) (Table 1). Orthopedic assessment indicated developmental dysplasia of the hips (DDH) with bilateral congenital hip dislocation that was more severe on the left side, accompanied by bilateral acetabular dysplasia and a smaller left femoral epiphysis. There were no signs of scoliosis, joint laxity, or other deformities. Cardiac assessment and echocardiography were normal excluding cardiac malformations.

Fig. 1 16p11.2 deleted region identified by whole exome sequencing.30 genes are shown to be encompassed in the deleted region (Chr16:29635211–30199850) [UCSC genome browser: GRCh37]: (including two pseudogenes (in pink) and one divergent transcript RNA gene (in green)

Table 1 Previous and current reports of chromosome 16p11.2 deletion syndrome in the Middle East and North Africa (MENA) region

Reports	[27]
Al-Hassnan et al., 2018	[28]
Al-Saud, 2013	[29]
Chehbani et al., 2022	Current Report
Elsayed et al.,	
Chromosome 16p11.2 deleted region	16p11.2;

29,567,295 − 30,321,320;

~ 754 Kb (hg19).

	16p11.2 deletion of 659,635 bp (Exact genomic location was not provided)	16p11.2; 29,652,999 − 30,197,341;

~ 545 Kb (hg19).

	Microarray:

16p11.2;

29,567,295 − 30,177,916;

~ 611 Kb (hg19)

WES:

16p11.2;

29,635,211 − 30,199,850;

~ 565 Kb (hg19).

	
Concomitant CNVs/chromosomal rearrangement	Balanced translocation: the q-arm of chromosome 10 and the q arm of chromosome 12

(46,XX, t(10;12)(q22;q22)

Deletion: chromosome 12 (12p12.1p11.21; 25,320,816–31,285,151; ~5.96 Mb)

	-	-	-	
Other variants	-	-	-	TYR gene Homozygous mutation [NM_000372.4:c.1205G > A (p.Arg402Gln)]

Identified by WES

	
Number of patients reported	1	2	1	1	
Patients Nationalities	Saudi	Saudi	Tunisian	Saudi	
Gender	F	NDA	M	F	
Inherited /De novo	Translocation chromosome 10/12) (probably inherited but not confirmed)

Chromosome 16 del. (paternally inherited)

Chromosome 12 del. (de novo)

	NDA	NDA	De novo	
Consanguineous parents	+	NDA	NDA	+	
Onset of clinical manifestations	Prenatal	NDA	Mostly at birth	Likely prenatal	
Age at examination	3 years	NDA	6 years	22 months	
Prenatal /Delivery/Neonatal manifestations	In vitro fertilization (delivery at 34 weeks)	NDA	Birth complications	• Complicated delivery (cesarean section) due to fetal distress and meconium-stained liquor

• Neonatal intensive care admission for three days

	
Intellectual disability/ neurocognitive delay	As part of the GDD	Mild mental retardation	+	As part of the GDD	
Developmental delay	GDD	NDA	+	GDD	
Language impairment	As part of the GDD	+	+	As part of the GDD	
Epilepsy/Seizure	-	NDA	-	+	
Neuropsychiatric disorders	-	Hyperactivity	Moderate ASD manifestations including severe social communication deficit and language delay with echolalia	No proper assessment could be done	
Head size	< 5th percentile (microcephaly)	NDA	NDA	< 3rd percentile (microcephaly)	
Other growth parameters (Height and weight)	< 5th percentile	Moderate Obesity	NDA	< 3rd percentile	
Dysmorphic Features	Low-set ears, depressed nasal bridge, and long philtrum	NDA	-	Low-set ears, retracted forehead and chin, prominent maxillae and occiput, and high-arched palates	
Congenital cardiac malformation	Septal defect (atrial & ventricular) Hypoplastic right upper pulmonary vein	NDA	-	-	
Other (non-cardiac) congenital malformations	-	NDA	-	Skeletal: DDH with bilateral congenital hip dislocation (more severe on the left side)	
Hyperphagia/ Obesity/Insulin resistance	-	Hyperphagia and

Moderate obesity (BMIs of 34.5 and 35.1 kg/m²)

	-	-	
Visual impairment	-	-	-	+	
Macular/optic disc coloboma	Left-sided	-	-	-	
Optic atrophy	-	-	-	+	
Axial hypotonia	-	-	-	+	
UL/LL pyramidal features	-	-	-	+	
Auditory impairment	-	-	-	+	
MRI findings	Normal	NDA	NDA	• Dandy-Walker spectrum

• Mild thinning of the splenium of corpus callosum

	
CNV: copy number variation, GDD: global developmental delay, DDH: developmental dysplasia of the hip, UL: upper limb, LL: lower limb, MRI: magnetic resonance imaging. NDA: No data available, M: male, F: female, (+): present, (-): Absent OA

Cognitive impairment was evident, characterized by limited interaction with her surroundings, corroborating parental observations. A formal cognitive assessment was challenging to perform. Neurological examination showed axial hypotonia with spasticity in both upper and lower limbs. Deep tendon reflexes were normal in the upper limbs but increased in both lower limbs with bilateral up-going plantar responses. The assessment of her power was affected by her disability; however, a minimum strength of 4 out of 5 was noted. Examination of the sensory, extrapyramidal, and cerebellar systems was not feasible due to her spasticity and marked disability. The ophthalmological assessment revealed poor visual fixation with response only to light only, normal anterior chamber, and a flat retina with optic atrophy, but no evidence of retinitis pigmentosa or retinal hypopigmentation.

Following an abnormal neonatal hearing screening (automated auditory brainstem response (AABR)), an auditory brainstem response (ABR) test revealed sensorineural hearing loss with absent Distortion Product Otoacoustic Emissions (DPOAE) and Transient Evoked Otoacoustic Emissions (TEOAE), normal middle ear and no evidence of conduction hearing loss. MRI of the brain showed mild thinning of the splenium of the corpus callosum. Additional features suggestive of the Dandy-Walker spectrum were identified. These included a small volume of the cerebellar vermis, cerebellum, and brain stem with enlargement of the retro-cerebellar subarachnoid space that communicates with the fourth ventricle. Moreover, pronounced Sylvian fissures and prominent frontal peri-cerebral cerebrospinal spaces were noted, likely attributable to microcephaly of the adjacent cerebral lobes (Fig. 1) (Table 1).

A prenatal onset of clinical presentation in our patient was hypothesized even though there were no ultrasound records documenting specific prenatal features. This hypothesis was supported by the presence of congenital microcephaly, bilateral DDH, as well as the Dandy-Walker spectrum, and the abnormal AABR detected shortly after birth. Further support to this suggestion was the complicated delivery (cesarean section) [due to fetal distress and meconium-stained liquor] followed by three days of admission to neonatal intensive care. In the 16p11.2 microdeletion syndrome, the prenatal onset of disease phenotype could be proposed in cases with congenital malformations and those with neonatal complications. However, a variety of fetal presentations were documented by ultrasonography including skeletal, cardiovascular, and neurological malformations among others [7, 24–26]. Detailed examination of the parents revealed no hypopigmentation or phenotypic features seen in the patient.

Genetic results

Microarray results

A heterozygous deletion of size 611 Kb was identified (arr[GRCh38]16p11.2 (29555974_30166595)x1) [(arr[GRCh37]16p11.2(29567295_30177916)x1)]. In addition, a significant absence of heterozygosity encompassing 5.97% of the autosomal genomic length (166,280 Kb) was detected indicating parental consanguinity (Supplementary Table S2).

WES results

A pathogenic interstitial one-copy loss of 565 Kb was detected using an NGS-based CNV analysis (arr[GRCh37]16p11.2(29635211_30199850)x1). The copy loss was within the chromosomal region 16p11.2 with 30 genes (including two pseudogenes and the entire TBX6 gene) involved in the deleted area (Fig. 2) (Supplementary Table S1). This NGS finding confirmed the results obtained by the chromosomal microarray (CMA) analysis. The deletion was absent in both parents suggesting it was a de novo CNV (Fig. 1) (Table 1). The region reported is identified as pathogenic in both Decipher and ClinVar databases. Additionally, WES identified a homozygous mutation TYR gene [NM_000372.4:c.1205G > A (p.Arg402Gln)] (Fig. 1). WES identified that the mother was homozygous and the father heterozygous for the same TYR gene mutation. The variant was reported in the literature as a hypomorphic allele associated with hypopigmentation. According to the criteria defined in the methods, no other putatively pathogenic variants (including structural variants) were found to segregate with the phenotype of the patient.

Fig. 2 Family pedigree, genetic, radiological, and clinical characterization of the patient. A Family pedigree showing the segregation of the chromosome 16p11.2 deletion identified by whole exome sequencing and microarray and TYR gene mutation [NM_000372.4:c.1205G > A (p.Arg402Gln)]. B MRI of the brain (T2 and T2 FLAIR axial and T1 sagittal views) showing a small volume of the cerebellum, and brain stem with enlargement of the retro-cerebellar subarachnoid space communicating with the fourth ventricle (suggestive of Dandy-Walker spectrum). Thin splenium of the corpus callosum, prominent Sylvian fissures, and frontal peri-cerebral cerebrospinal spaces are also evident.C High-arched palate (C1), low-set ears (C2), microcephaly (C1-C3), and hypopigmented macules and plaques on the dorsum hand (C4)

Discussion

Even though 16p11.2 microdeletion syndrome is relatively common among CNV-associated disorders, it was detected in only four studies from the MENA region collectively reporting 4 cases, with 3 cases from Saudi Arabia and one from Tunisia [27–29]. We are reporting the 8th case of 16p11.2 deletion in the region, a Saudi girl who presented with a complex neurological phenotype associated with loss of skin and hair pigmentation – probably due to an involvement of a TYR gene hypomorphic polymorphism.

Our report supports the deep effect of genetic studies conducted in the MENA region on the understanding of many disorders despite the relative insufficiency of the published data. Two of the Saudi patients had obesity, mild mental retardation, hyperphagia, language delay, and hyperactivity [28]. The last had a combination of two deletions on chromosomes 12 and 16 [a de novo 12p12.1p11.21 and inherited 16p11.2. deletion] presenting with a complex phenotype that partially overlaps with the phenotype observed in our patient [GDD, failure to thrive, dysmorphic features, macular and optic disc coloboma, septal defects] [27].

The clinical picture of our patient relatively matched the described 16p11.2 deletion syndrome phenotypic presentation with some unique features that expand the known phenotypic spectrum of the syndrome. Developmental delay at variable degrees and speech deficit are considered among the commonest presentations of the 16p11.2 deletion syndrome occurring in > 90% and > 70% of the patients, respectively. On the other hand, deafness is considered a rare manifestation of 16p11.2 microdeletion syndrome (< 11%) with less than 10 cases reported to date [7, 10, 30–34].

Myoclonic seizures are extremely rare although seizures and epilepsy are reported in around 24–38% and 18% of individuals with chromosome 16p11.2 deletion, respectively [7, 35]. In a cohort of 129 individuals with 16p11.2 deletion syndrome, myoclonic jerks were found in one patient only whereas overall the focal seizures constituted 55% of the reported seizure cases with a predominance of focal tonic/tonic-clonic (29%). Additionally, tonic-clonic seizures of unknown onset were observed in 29% of cases. The onset of epilepsy during the first year of life was common, occurring in 61% of individuals, which aligns with our observations [12, 35]. The deleted region spans PRRT2, the loss of which predisposes to seizure and movement disorders [OMIM * 614386].

Although 16p11.2 has been strongly associated with obesity and hyperphagia, the failure to thrive and abnormally decreased weight that was observed in our patient match what has been described in some reports as well. However, our patient was younger than the age at onset (2 years) of hyperphagia and the consequent obesity that was described by Szelest et al. and a few other reports [7, 10, 12, 31, 36, 37].

A variety of congenital malformations was described in 16p11.2 deletion syndrome, with a relatively high overall average rate of occurrence of 30–31% with remarkable variations observed according to the type of the congenital anomaly and the system involved [7, 26, 33]. Remarkably, none of the commonly encountered malformations was detected in our patient who had instead bilateral DDH. DDH was not previously linked to chromosome 16p11.2 deletion which makes our patient the first case reported.

It is noteworthy that the combination of microcephaly and Dandy-Walker spectrum as a part of the presentation of 16p11.2 microdeletion syndrome is quite a rare incidence as both were very rarely described in association with the deletion in addition to the rarity of their combination. Microcephaly was very rarely described in patients with 16p11.2 deletion with our patient being the seventh case reported to present [26, 38, 39]. In previous cohorts, microcephaly was associated with 16p11.2 duplication with deletions significantly associated with absolute or relative macrocephaly [7, 10, 36, 40]. Although posterior fossa and cerebellar malformations, particularly, Chiari I/cerebellar tonsillar ectopia, were relatively commonly associated with 16p11.2 microdeletion syndrome in numerous previous reports [8, 32, 39, 41, 42], however; Dandy-Walker malformation was reported in one case only before our current report [26]. Moreover, the combination of microcephaly with Dandy-Walker spectrum malformation is remarkable since the latter was known to be more frequently associated with macrocrania and hydrocephalus [43]. The microcephaly associated with the 16p11.2 duplication and the macrocephaly associated with the deletion were attributed by Golzio et al. to the overexpression and the suppression of the KCTD13 gene (one of the genes included in the deletion region) implying a dosage effect of the KCTD13 protein [44]. This contradiction with the classical presentation of macrocephaly and the proposed role of KCTD13 protein may be attributed to differences in background genetics and the presence of genetic modifiers. It can add up to the known phenotypic heterogeneity described in the 16p11.2 deletion and the extreme variability of its associated clinical presentations. Future functional studies may provide a molecular explanation of the occurrence of microcephaly and open a new area in research.

The 16p11.2 microdeletion syndrome is associated with a range of ocular manifestations, however, there were no previous records of its association with optic atrophy and flat retina [45, 46].

Limited dermatological features have been associated with chromosome 16p11.2 deletion, with café au lait spots being among the few reported pigmentary disturbances. The hypopigmentation and depigmentation observed in our patient may be attributed to the identified homozygous mutation TYR p.Arg402Gln [rs1126809]. This substitution has been frequently described as a hypomorphic allele resulting in a thermolabile tyrosinase enzyme. It produces a peptide that is subject to retention by the endoplasmic reticulum with consequent reduction of its catalytic activity to 25% of that of the wildtype enzyme at 37º C. It has been reported to contribute to the pathogenesis of albinism especially when associated with other heterozygous pathogenic mutations [47–49]. Given the mild phenotype observed in our patient, characterized by dispersed regions of hypopigmentation despite its progressive nature, we propose that the substitution may have played a role in the pathogenesis of the condition. [47–49]. However, the absence of hypopigmentation in the mother who was also homozygous for the same TYR variant contradicts the complete attribution of the pigmentary lesions to the variant only. Although further workup may be needed to understand the exact underlying mechanism, there may have been a contribution of an interaction of the p.Arg402Gln variant with the 16p11.2 deletion or any other modifier variant that might not have been detected.

Limitations

The origin of the patient consanguineous family with several loops of consanguinity over multiple generations and long runs of homozygosity identified upon genetic analysis might be associated with the presence of pathogenic mutations in a homozygous state that might not have been identified which is especially true for variants in non-coding/regulatory regions and for novel genes. This could have an important impact on the patient’s phenotypic presentation since the population in which the patient originated is considered relatively genetically underexplored.

This is particularly evident when considering the pathogenesis of the hypo-pigmentary lesions. Both the healthy mother and the affected patient carry the same homozygous p.Arg402Gln variant, suggesting the presence of an unidentified genetic modifier. This reasoning may also extend to other rare manifestations observed in the patient. Thorough investigation of the medical history of the nuclear and extended family, along with comprehensive genetic data analysis, could help to address this challenge, at least in part.

Conclusions

In this report, we expand the clinical phenotype associated with proximal 16p11.2 microdeletion syndrome to include DDH, optic atrophy, flat retina, Dandy-Walker spectrum, and TCC. Furthermore, we are reporting one of the exceptionally scarce cases of microcephaly in association with 16p11.2 deletion. Our patient also exhibited other rare presentations, including myoclonic epilepsy and deafness. This case report further highlights the potential of genetic research in Saudi Arabia and the MENA region emphasizing the importance of further studies to explore the genetic background and understand the causes of the unique features observed in our patient.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Acknowledgements

We thank the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University for their support and funding of the research.

Author contributions

LEOE, NAA, AMA, HEE, MAA, AMB, FAA, HMA, AMM, and OAA formulated and designed the study. LEOE, AMA, HEE, NMMM, MMA, and FAA granted funds. LEOE, NAA, AMA, HEE, NMMM, MMA, HIBZ, LMA, SAA, KA, SYA, HYA, FAA, HAR, HMA, AMM, and OAA contributed to the sampling, clinical, radiologic, and ethnological data collection and interpretation. LEOE, NAA, HEE, HAR, MAKO, AMM, and OAA contributed to the genetic data analysis, WES and microarray data bioinformatics analysis, and the drafting and revision of the manuscript. All authors read and approved the manuscript, assented to its submission, agreed to be responsible for all aspects of this work, and agreed to be personally accountable for their contributions.

Funding

This research was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University, through the Research Funding Program, Grant No. (FRP-1443-5).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

The study was approved by the Institutional Review Board of Princess Nourah bint Abdulrahman University, Saudi Arabia (IRB Log Number: 20–0150) according to the recommendations of the Helsinki Declaration. Written informed consent to participate in this study was provided by all the adult participants and the legal guardian (father) of the child.

Consent for publication

Written informed consent was also obtained for the publication of the results and any potentially identifiable images or data included in this article.

Competing interests

The authors declare no competing interests.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Aguirre M Rivas MA Priest J Phenome-wide Burden of Copy-number variation in the UK Biobank Am J Hum Genet 2019 105 373 83 10.1016/j.ajhg.2019.07.001 31353025
Aguirre M, Rivas MA, Priest J. Phenome-wide Burden of Copy-number variation in the UK Biobank. Am J Hum Genet. 2019;105:373–83.31353025 10.1016/j.ajhg.2019.07.001
2. Kaminsky EB Kaul V Paschall J Church DM Bunke B Kunig D An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities Genet Med off J Am Coll Med Genet 2011 13 777 84
Kaminsky EB, Kaul V, Paschall J, Church DM, Bunke B, Kunig D, et al. An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genet Med off J Am Coll Med Genet. 2011;13:777–84.
3. Auwerx C Lepamets M Sadler MC Patxot M Stojanov M Baud D The individual and global impact of copy-number variants on complex human traits Am J Hum Genet 2022 109 647 68 10.1016/j.ajhg.2022.02.010 35240056
Auwerx C, Lepamets M, Sadler MC, Patxot M, Stojanov M, Baud D, et al. The individual and global impact of copy-number variants on complex human traits. Am J Hum Genet. 2022;109:647–68.35240056 10.1016/j.ajhg.2022.02.010
4. Smajlagić D Lavrichenko K Berland S Helgeland Ø Knudsen GP Vaudel M Population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders in 12,252 newborns and their parents Eur J Hum Genet 2021 29 205 15 10.1038/s41431-020-00707-7 32778765
Smajlagić D, Lavrichenko K, Berland S, Helgeland Ø, Knudsen GP, Vaudel M, et al. Population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders in 12,252 newborns and their parents. Eur J Hum Genet. 2021;29:205–15.32778765 10.1038/s41431-020-00707-7
5. Oliva-Teles N de Stefano MC Gallagher L Rakic S Jorge P Cuturilo G Rare pathogenic Copy Number Variation in the 16p11.2 (BP4-BP5) Region Associated with Neurodevelopmental and Neuropsychiatric disorders: a review of the literature Int J Environ Res Public Health 2020 17 9253 10.3390/ijerph17249253 33321999
Oliva-Teles N, de Stefano MC, Gallagher L, Rakic S, Jorge P, Cuturilo G, et al. Rare pathogenic Copy Number Variation in the 16p11.2 (BP4-BP5) Region Associated with Neurodevelopmental and Neuropsychiatric disorders: a review of the literature. Int J Environ Res Public Health. 2020;17:9253.33321999 10.3390/ijerph17249253
6. Orphanet. Orphanet: an online database of rare diseases and orphan drugs [Internet]. 2023 [cited 2023 Sep 22]. http://www.orpha.net
7. Shinawi M Liu P Kang S-HL Shen J Belmont JW Scott DA Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size J Med Genet 2010 47 332 41 10.1136/jmg.2009.073015 19914906
Shinawi M, Liu P, Kang S-HL, Shen J, Belmont JW, Scott DA, et al. Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. J Med Genet. 2010;47:332–41.19914906 10.1136/jmg.2009.073015
8. Zufferey F Sherr EH Beckmann ND Hanson E Maillard AM Hippolyte L A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders J Med Genet 2012 49 660 8 10.1136/jmedgenet-2012-101203 23054248
Zufferey F, Sherr EH, Beckmann ND, Hanson E, Maillard AM, Hippolyte L, et al. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. J Med Genet. 2012;49:660–8.23054248 10.1136/jmedgenet-2012-101203
9. Marshall CR Noor A Vincent JB Lionel AC Feuk L Skaug J Structural variation of chromosomes in Autism Spectrum Disorder Am J Hum Genet 2008 82 477 88 10.1016/j.ajhg.2007.12.009 18252227
Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, et al. Structural variation of chromosomes in Autism Spectrum Disorder. Am J Hum Genet. 2008;82:477–88.18252227 10.1016/j.ajhg.2007.12.009
10. Chung WK Roberts TP Sherr EH Snyder LG Spiro JE 16p11.2 deletion syndrome Curr Opin Genet Dev 2021 68 49 56 10.1016/j.gde.2021.01.011 33667823
Chung WK, Roberts TP, Sherr EH, Snyder LG, Spiro JE. 16p11.2 deletion syndrome. Curr Opin Genet Dev. 2021;68:49–56.33667823 10.1016/j.gde.2021.01.011
11. Stoppel LJ Kazdoba TM Schaffler MD Preza AR Heynen A Crawley JN R-Baclofen reverses cognitive deficits and improves social interactions in two lines of 16p11.2 deletion mice Neuropsychopharmacology 2018 43 513 24 10.1038/npp.2017.236 28984295
Stoppel LJ, Kazdoba TM, Schaffler MD, Preza AR, Heynen A, Crawley JN, et al. R-Baclofen reverses cognitive deficits and improves social interactions in two lines of 16p11.2 deletion mice. Neuropsychopharmacology. 2018;43:513–24.28984295 10.1038/npp.2017.236
12. Szelest M Stefaniak M Ręka G Jaszczuk I Lejman M Three case reports of patients indicating the diversity of molecular and clinical features of 16p11.2 microdeletion anomaly BMC Med Genomics 2021 14 76 10.1186/s12920-021-00929-8 33691695
Szelest M, Stefaniak M, Ręka G, Jaszczuk I, Lejman M. Three case reports of patients indicating the diversity of molecular and clinical features of 16p11.2 microdeletion anomaly. BMC Med Genomics. 2021;14:76.33691695 10.1186/s12920-021-00929-8
13. Weiss LA Shen Y Korn JM Arking DE Miller DT Fossdal R Association between Microdeletion and Microduplication at 16p11.2 and Autism N Engl J Med 2008 358 667 75 10.1056/NEJMoa075974 18184952
Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, et al. Association between Microdeletion and Microduplication at 16p11.2 and Autism. N Engl J Med. 2008;358:667–75.18184952 10.1056/NEJMoa075974
14. Crawford K Bracher-Smith M Owen D Kendall KM Rees E Pardiñas AF Medical consequences of pathogenic CNVs in adults: analysis of the UK Biobank J Med Genet 2019 56 131 8 10.1136/jmedgenet-2018-105477 30343275
Crawford K, Bracher-Smith M, Owen D, Kendall KM, Rees E, Pardiñas AF, et al. Medical consequences of pathogenic CNVs in adults: analysis of the UK Biobank. J Med Genet. 2019;56:131–8.30343275 10.1136/jmedgenet-2018-105477
15. Owen D Bracher-Smith M Kendall KM Rees E Einon M Escott-Price V Effects of pathogenic CNVs on physical traits in participants of the UK Biobank BMC Genomics 2018 19 867 10.1186/s12864-018-5292-7 30509170
Owen D, Bracher-Smith M, Kendall KM, Rees E, Einon M, Escott-Price V, et al. Effects of pathogenic CNVs on physical traits in participants of the UK Biobank. BMC Genomics. 2018;19:867.30509170 10.1186/s12864-018-5292-7
16. Levy B Wapner R Prenatal diagnosis by chromosomal microarray analysis Fertil Steril 2018 109 201 12 10.1016/j.fertnstert.2018.01.005 29447663
Levy B, Wapner R. Prenatal diagnosis by chromosomal microarray analysis. Fertil Steril. 2018;109:201–12.29447663 10.1016/j.fertnstert.2018.01.005
17. van Ravenswaaij-Arts CMA, van Der Sikkema-Raddatz B, Dijkhuizen T, Hanemaaijer NM, Hordijk R et al. Practical guidelines for interpreting copy number gains detected by high-resolution array CGH in routine diagnostics. Eur J Hum Genet [Internet]. 2011 [cited 2024 Jul 10]; https://hal.science/hal-00681221
18. Cooper GM Coe BP Girirajan S Rosenfeld JA Vu T Baker C A Copy Number Variation Morbidity Map of Developmental Delay Nat Genet 2011 43 838 46 10.1038/ng.909 21841781
Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu T, Baker C, et al. A Copy Number Variation Morbidity Map of Developmental Delay. Nat Genet. 2011;43:838–46.21841781 10.1038/ng.909
19. Coe BP Witherspoon K Rosenfeld JA Van Bon BWM Vulto-van Silfhout AT Bosco P Refining analyses of copy number variation identifies specific genes associated with developmental delay Nat Genet 2014 46 1063 71 10.1038/ng.3092 25217958
Coe BP, Witherspoon K, Rosenfeld JA, Van Bon BWM, Vulto-van Silfhout AT, Bosco P, et al. Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat Genet. 2014;46:1063–71.25217958 10.1038/ng.3092
20. Massadeh S Albeladi M Albesher N Alhabshan F Kampe KD Chaikhouni F Novel autosomal recessive splice-altering variant in PRKD1 is Associated with congenital heart disease Genes 2021 12 612 10.3390/genes12050612 33919081
Massadeh S, Albeladi M, Albesher N, Alhabshan F, Kampe KD, Chaikhouni F, et al. Novel autosomal recessive splice-altering variant in PRKD1 is Associated with congenital heart disease. Genes. 2021;12:612.33919081 10.3390/genes12050612
21. Magi A Tattini L Palombo F Benelli M Gialluisi A Giusti B H3M2: detection of runs of homozygosity from whole-exome sequencing data Bioinforma Oxf Engl 2014 30 2852 9 10.1093/bioinformatics/btu401
Magi A, Tattini L, Palombo F, Benelli M, Gialluisi A, Giusti B, et al. H3M2: detection of runs of homozygosity from whole-exome sequencing data. Bioinforma Oxf Engl. 2014;30:2852–9.10.1093/bioinformatics/btu401
22. Fowler A Mahamdallie S Ruark E Seal S Ramsay E Clarke M Accurate clinical detection of exon copy number variants in a targeted NGS panel using DECoN Wellcome Open Res 2016 1 20 10.12688/wellcomeopenres.10069.1 28459104
Fowler A, Mahamdallie S, Ruark E, Seal S, Ramsay E, Clarke M, et al. Accurate clinical detection of exon copy number variants in a targeted NGS panel using DECoN. Wellcome Open Res. 2016;1:20.28459104 10.12688/wellcomeopenres.10069.1
23. Geoffroy V Herenger Y Kress A Stoetzel C Piton A Dollfus H AnnotSV: an integrated tool for structural variations annotation Bioinforma Oxf Engl 2018 34 3572 4 10.1093/bioinformatics/bty304
Geoffroy V, Herenger Y, Kress A, Stoetzel C, Piton A, Dollfus H, et al. AnnotSV: an integrated tool for structural variations annotation. Bioinforma Oxf Engl. 2018;34:3572–4.10.1093/bioinformatics/bty304
24. Lin S Shi S Zhou Y Ji Y Huang P Wu J Intrauterine phenotypic features associated with 16p11.2 recurrent microdeletions Prenat Diagn 2018 38 381 9 10.1002/pd.5245 29514395
Lin S, Shi S, Zhou Y, Ji Y, Huang P, Wu J, et al. Intrauterine phenotypic features associated with 16p11.2 recurrent microdeletions. Prenat Diagn. 2018;38:381–9.29514395 10.1002/pd.5245
25. Tao H, Wu J, Han Y, Zhang B, Zhai J. Genetic etiology and pregnancy outcomes of fetuses with central nervous system anomalies. Arch Gynecol Obstet [Internet]. 2023 [cited 2023 Aug 10]; 10.1007/s00404-023-07152-z
26. Wang Y Zhou H Fu F Cheng K Yu Q Huang R Prenatal diagnosis of chromosome 16p11.2 Microdeletion Genes 2022 13 2315 10.3390/genes13122315 36553582
Wang Y, Zhou H, Fu F, Cheng K, Yu Q, Huang R, et al. Prenatal diagnosis of chromosome 16p11.2 Microdeletion. Genes. 2022;13:2315.36553582 10.3390/genes13122315
27. Al-Hassnan ZN Albawardi W Almutairi F AlMass R AlBakheet A Mustafa OM Identification of novel genomic imbalances in Saudi patients with congenital heart disease Mol Cytogenet 2018 11 9 10.1186/s13039-018-0356-6 29416564
Al-Hassnan ZN, Albawardi W, Almutairi F, AlMass R, AlBakheet A, Mustafa OM, et al. Identification of novel genomic imbalances in Saudi patients with congenital heart disease. Mol Cytogenet. 2018;11:9.29416564 10.1186/s13039-018-0356-6
28. Al-Saud H. The genetics of obesity in Saudi Arabian population. 2013 [cited 2023 Aug 5]; http://spiral.imperial.ac.uk/handle/10044/1/25989
29. Chehbani F Tomaiuolo P Picinelli C Baccarin M Castronovo P Scattoni ML Yield of array-CGH analysis in Tunisian children with autism spectrum disorder Mol Genet Genomic Med 2022 10 e1939 10.1002/mgg3.1939 35762097
Chehbani F, Tomaiuolo P, Picinelli C, Baccarin M, Castronovo P, Scattoni ML, et al. Yield of array-CGH analysis in Tunisian children with autism spectrum disorder. Mol Genet Genomic Med. 2022;10:e1939.35762097 10.1002/mgg3.1939
30. Hanson E Nasir RH Fong A Lian A Hundley R Shen Y Cognitive and behavioral characterization of 16p11.2 deletion syndrome J Dev Behav Pediatr JDBP 2010 31 649 57 10.1097/DBP.0b013e3181ea50ed 20613623
Hanson E, Nasir RH, Fong A, Lian A, Hundley R, Shen Y, et al. Cognitive and behavioral characterization of 16p11.2 deletion syndrome. J Dev Behav Pediatr JDBP. 2010;31:649–57.20613623 10.1097/DBP.0b013e3181ea50ed
31. Rosenfeld JA Coppinger J Bejjani BA Girirajan S Eichler EE Shaffer LG Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications J Neurodev Disord 2010 2 26 38 10.1007/s11689-009-9037-4 21731881
Rosenfeld JA, Coppinger J, Bejjani BA, Girirajan S, Eichler EE, Shaffer LG, et al. Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications. J Neurodev Disord. 2010;2:26–38.21731881 10.1007/s11689-009-9037-4
32. Schaaf CP Goin-Kochel RP Nowell KP Hunter JV Aleck KA Cox S Expanding the clinical spectrum of the 16p11.2 chromosomal rearrangements: three patients with syringomyelia Eur J Hum Genet EJHG 2011 19 152 6 10.1038/ejhg.2010.168 20959866
Schaaf CP, Goin-Kochel RP, Nowell KP, Hunter JV, Aleck KA, Cox S, et al. Expanding the clinical spectrum of the 16p11.2 chromosomal rearrangements: three patients with syringomyelia. Eur J Hum Genet EJHG. 2011;19:152–6.20959866 10.1038/ejhg.2010.168
33. Taylor CM, Smith R, Lehman C, Mitchel MW, Singer K, Weaver WC et al. 16p11.2 Recurrent Deletion. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [cited 2023 Sep 12]. http://www.ncbi.nlm.nih.gov/books/NBK11167/
34. Yang M Mahrt EJ Lewis F Foley G Portmann T Dolmetsch RE 16p11.2 deletion syndrome mice display sensory and Ultrasonic vocalization deficits during social interactions Autism Res off J Int Soc Autism Res 2015 8 507 21 10.1002/aur.1465
Yang M, Mahrt EJ, Lewis F, Foley G, Portmann T, Dolmetsch RE, et al. 16p11.2 deletion syndrome mice display sensory and Ultrasonic vocalization deficits during social interactions. Autism Res off J Int Soc Autism Res. 2015;8:507–21.10.1002/aur.1465
35. Achkar ME Rosen C Kessler A Steinman SK Spence KJ Ramocki SJ Clinical characteristics of seizures and Epilepsy in individuals with recurrent deletions and duplications in the 16p11.2 region Neurol Genet 2022 8 e200018 10.1212/NXG.0000000000200018 36531974
Achkar ME, Rosen C, Kessler A, Steinman SK, Spence KJ, Ramocki SJ. Clinical characteristics of seizures and Epilepsy in individuals with recurrent deletions and duplications in the 16p11.2 region. Neurol Genet. 2022;8:e200018.36531974 10.1212/NXG.0000000000200018
36. Rein B Yan Z 16p11.2 Copy Number variations and Neurodevelopmental disorders Trends Neurosci 2020 43 886 901 10.1016/j.tins.2020.09.001 32993859
Rein B, Yan Z. 16p11.2 Copy Number variations and Neurodevelopmental disorders. Trends Neurosci. 2020;43:886–901.32993859 10.1016/j.tins.2020.09.001
37. Walters RG Jacquemont S Valsesia A de Smith AJ Martinet D Andersson J A novel highly-penetrant form of obesity due to microdeletions on chromosome 16p11.2 Nature 2010 463 671 5 10.1038/nature08727 20130649
Walters RG, Jacquemont S, Valsesia A, de Smith AJ, Martinet D, Andersson J, et al. A novel highly-penetrant form of obesity due to microdeletions on chromosome 16p11.2. Nature. 2010;463:671–5.20130649 10.1038/nature08727
38. Bijlsma EK Gijsbers ACJ Schuurs-Hoeijmakers JHM van Haeringen A van de Fransen DE Anderlid B-M Extending the phenotype of recurrent rearrangements of 16p11.2: deletions in mentally retarded patients without autism and in normal individuals Eur J Med Genet 2009 52 77 87 10.1016/j.ejmg.2009.03.006 19306953
Bijlsma EK, Gijsbers ACJ, Schuurs-Hoeijmakers JHM, van Haeringen A, van de Fransen DE, Anderlid B-M, et al. Extending the phenotype of recurrent rearrangements of 16p11.2: deletions in mentally retarded patients without autism and in normal individuals. Eur J Med Genet. 2009;52:77–87.19306953 10.1016/j.ejmg.2009.03.006
39. Steinman KJ Spence SJ Ramocki MB Proud MB Kessler SK Marco EJ 16p11.2 deletion and duplication: characterizing neurologic phenotypes in a large clinically ascertained cohort Am J Med Genet A 2016 170 2943 55 10.1002/ajmg.a.37820 27410714
Steinman KJ, Spence SJ, Ramocki MB, Proud MB, Kessler SK, Marco EJ, et al. 16p11.2 deletion and duplication: characterizing neurologic phenotypes in a large clinically ascertained cohort. Am J Med Genet A. 2016;170:2943–55.27410714 10.1002/ajmg.a.37820
40. Fetit R Price DJ Lawrie SM Johnstone M Understanding the clinical manifestations of 16p11.2 deletion syndrome: a series of developmental case reports in children Psychiatr Genet 2020 30 136 40 10.1097/YPG.0000000000000259 32732550
Fetit R, Price DJ, Lawrie SM, Johnstone M. Understanding the clinical manifestations of 16p11.2 deletion syndrome: a series of developmental case reports in children. Psychiatr Genet. 2020;30:136–40.32732550 10.1097/YPG.0000000000000259
41. D’Angelo D Lebon S Chen Q Martin-Brevet S Snyder LG Hippolyte L Defining the Effect of the 16p11.2 duplication on Cognition, Behavior, and medical comorbidities JAMA Psychiatry 2016 73 20 30 10.1001/jamapsychiatry.2015.2123 26629640
D’Angelo D, Lebon S, Chen Q, Martin-Brevet S, Snyder LG, Hippolyte L, et al. Defining the Effect of the 16p11.2 duplication on Cognition, Behavior, and medical comorbidities. JAMA Psychiatry. 2016;73:20–30.26629640 10.1001/jamapsychiatry.2015.2123
42. Owen JP, Bukshpun P, Pojman N, Thieu T, Chen Q, Lee J et al. Brain MR Imaging Findings and Associated Outcomes in Carriers of the Reciprocal Copy Number Variation at 16p11.2. Radiology [Internet]. 2017 [cited 2023 Aug 15]; 10.1148/radiol.2017162934
43. Spennato P, Cascone D, Di Martino G, Mirone G, Ruggiero C, Cinalli G. Dandy–Walker Malformations/Variants. In: Di Rocco C, Pang D, Rutka JT, editors. Textb Pediatr Neurosurg [Internet]. Cham: Springer International Publishing; 2018 [cited 2024 Jul 20]. pp. 1–33. 10.1007/978-3-319-31512-6_40-1
44. Golzio C Willer J Talkowski ME Oh EC Taniguchi Y Jacquemont S KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant Nature 2012 485 363 7 10.1038/nature11091 22596160
Golzio C, Willer J, Talkowski ME, Oh EC, Taniguchi Y, Jacquemont S, et al. KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. Nature. 2012;485:363–7.22596160 10.1038/nature11091
45. Bardakjian TM Kwok S Slavotinek AM Schneider AS Clinical report of microphthalmia and optic nerve coloboma associated with a de novo microdeletion of chromosome 16p11.2 Am J Med Genet A 2010 152A 3120 3 10.1002/ajmg.a.33492 21082658
Bardakjian TM, Kwok S, Slavotinek AM, Schneider AS. Clinical report of microphthalmia and optic nerve coloboma associated with a de novo microdeletion of chromosome 16p11.2. Am J Med Genet A. 2010;152A:3120–3.21082658 10.1002/ajmg.a.33492
46. Stingl CS Jackson-Cook C Couser NL Ocular findings in the 16p11.2 Microdeletion Syndrome: a Case Report and Literature Review Case Rep Pediatr 2020 2020 2031701 32373379
Stingl CS, Jackson-Cook C, Couser NL. Ocular findings in the 16p11.2 Microdeletion Syndrome: a Case Report and Literature Review. Case Rep Pediatr. 2020;2020:2031701.32373379
47. Chiang P-W Drautz JM Tsai AC-H Spector E Clericuzio CL A new hypothesis of OCA1B Am J Med Genet A 2008 146A 2968 70 10.1002/ajmg.a.32539 18925668
Chiang P-W, Drautz JM, Tsai AC-H, Spector E, Clericuzio CL. A new hypothesis of OCA1B. Am J Med Genet A. 2008;146A:2968–70.18925668 10.1002/ajmg.a.32539
48. Fukai K Holmes SA Lucchese NJ Mok Siu V Weleber RG Schnur RE Autosomal recessive ocular albinism associated with a functionally significant tyrosinase gene polymorphism Nat Genet 1995 9 92 5 10.1038/ng0195-92 7704033
Fukai K, Holmes SA, Lucchese NJ, Mok Siu V, Weleber RG, Schnur RE, et al. Autosomal recessive ocular albinism associated with a functionally significant tyrosinase gene polymorphism. Nat Genet. 1995;9:92–5.7704033 10.1038/ng0195-92
49. Hutton SM Spritz RA A comprehensive genetic study of autosomal recessive ocular albinism in caucasian patients Invest Ophthalmol Vis Sci 2008 49 868 72 10.1167/iovs.07-0791 18326704
Hutton SM, Spritz RA. A comprehensive genetic study of autosomal recessive ocular albinism in caucasian patients. Invest Ophthalmol Vis Sci. 2008;49:868–72.18326704 10.1167/iovs.07-0791
