Chromosome 16p11.2 microdeletion syndrome with microcephaly and Dandy-Walker malformation spectrum: expanding the known phenotype

• Published in: Human genomics Vol. 18; no. 1; pp. 95 - 10
• Main Authors: Elsayed, Liena Elbaghir Omer, AlHarbi, Norah Ayed, Alqarni, Ashwaq Mohammed, Eltayeb, Huda Hussein Elwasila, Mostafa, Noura Mostafa Mohamed, Abdulrahim, Maha Mohammed, Zaid, Hadeel Ibrahim Bin, Alanzi, Latifah Mansour, Ababtain, Sarah Abdullah, Aldulaijan, Khawlah, Aloyouni, Sheka Yagub, Othman, Moneeb Abdullah Kassem, Alkheilewi, Mohammad Abdullah, Binduraihem, Adel Mohammed, Alrukban, Hadeel Abdollah, Ahmed, Hiba Yousif, AlRadini, Faten Abdullah, Alahdal, Hadil Mohammad, Mushiba, Aziza Mufareh, Alzaher, Omaima Abdulazeem
• Format: Journal Article
• Language: English
• Published: England BioMed Central 04-09-2024; BMC
• Subjects: Atrophy; Autism; Autistic Disorder; Child; Child, Preschool; Chromosome 16; Chromosome Deletion; Chromosome Disorders - genetics; Chromosome Disorders - pathology; Chromosomes; Chromosomes, Human, Pair 16 - genetics; Cognition; Cognitive ability; Cognitive impairment; Congenital defects; Congenital diseases; Convulsions & seizures; Copy number; Corpus callosum; Dandy-Walker Syndrome - complications; Dandy-Walker Syndrome - genetics; Dandy-Walker Syndrome - pathology; de novo; Deafness; DNA Copy Number Variations - genetics; DNA microarrays; Epilepsy; Female; Genetic disorders; Genomes; Genotype & phenotype; Global developmental delay; Humans; Insulin resistance; Intellectual disabilities; Intellectual Disability - genetics; Intellectual Disability - pathology; Male; Mental disorders; Microcephaly; Microcephaly - complications; Microcephaly - genetics; Microcephaly - pathology; Microencephaly; Mitochondrial DNA; Optic atrophy; Orthopedics; Pediatrics; Phenotype; Phenotypes; Phenotypic variations; Pigmentation; Recurrent proximal chromosome 16p11.2 microdeletion syndrome; Saudi Arabia; Sensorimotor integration; TYR gene; Whole genome sequencing; Saudi Arabia; Saudi Arabia; Myoclonic epilepsy; Global developmental delay; Optic atrophy; de novo; Dandy-walker spectrum; Recurrent proximal chromosome 16p11.2 microdeletion syndrome; Microcephaly; Cognitive impairment
• ISSN: 1479-7364; 1473-9542; 1479-7364
• DOI: 10.1186/s40246-024-00662-0

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.
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.
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.