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

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.

A Novel De Novo Mutation of the DHX30 Gene in a Patient With Neurodevelopmental Disorder, Severe Motor Impairment, and Absent Language (NEDMIAL).

INTRODUCTION:  DExH-Box Helicase 30 (DHX30) is a gene that codes for proteins. It belongs to the class of RNA secondary structure unwinding helicases known as DExH-boxes. There have been numerous reports of pathogenic DHX30 variants. Most mutations, but not all, result in severe phenotypic abnormalities. The most common symptoms are severe motor developmental delay, intellectual disability, sleep disturbances, autism spectrum disorder, seizures, and gait abnormalities. OBJECTIVE: The objectives of reporting this case are: To report a novel mutation giving rise to NEDMIAL and to update the literature regarding the manifestation of the case of a rare condition (NEDMIAL). CASE PRESENTATION:  We report the case of a 12-year-old female who presented with similar complaints of severe motor impairment, seizures, intellectual disability, and absent language and was later diagnosed on Next-Generation Sequencing (NGS) with an autosomal dominant neurodevelopmental disorder (NEDMIAL). CONCLUSION:  We report a case of neurodevelopmental disorder with severe motor impairment and absent language (NEDMIAL) with a De novo novel DHX30 mutation (p.Pro796Leu) detected by whole exome sequence. We suggest upgrading the variant classification of DHX30:p.Pro796Leu to likely pathogenic, according to the evidence found in our patient. To the best of our knowledge, this is the first reported case of this mutation and disorder in the Middle East.

A Novel SCNN1A Variation in a Patient with Autosomal-recessive Pseudohypoaldosteronism Type 1

Pseudohypoaldosteronism type 1 (PHA1) is an autosomal-recessive disorder characterized by defective regulation of body sodium (Na) levels. The abnormality results from mutations in the genes encoding subunits of the epithelial Na channel. Patients with PHA1 present in infancy as being in adrenal crisis. A 41-day-old female who presented with recurrent adrenal crisis did not adequately respond to hydrocortisone and required mineralocorticoid therapy. The patient's demographic data and clinical features were recorded. Blood samples were collected and tested for endocrine and metabolic characteristics and for use in genetic studies. Bidirectional Sanger sequencing of SCNN1A was conducted. The entire coding region of 12 exons and 20 bp of flanking intron were sequenced. Genetic analyses revealed a new mutation - c.729_730delAG (p.Val245Glyfs*65) - in SCNN1A exon four. Adrenal crisis during the neonatal period highlights the importance of early screening for PHA1. Genetic testing could help to anticipate the prognosis, severity, onset of the disease, and the mode of inheritance, especially given its extensive phenotype.

The genotypic and phenotypic spectrum of pycnodysostosis in Saudi Arabia: Novel variants and clinical findings.

Pycnodysostosis is characterized by short stature, osteosclerosis, acro-osteolysis, increased tendency of fractures, and distinctive dysmorphic features. It is a rare autosomal recessive disease caused by biallelic CTSK mutations. The clinical details of 18 patients from Saudi Arabia were reviewed. Short stature, osteopetrosis, acro-osteolysis, and distinctive facial dysmorphism were documented in all cases. Our results highlight the significant complications associated with this disease. The large anterior fontanelle is one of the cardinal signs of this disease; however, half of our patients had small fontanelles and a quarter had craniosynostosis, which caused optic nerve compression. Sleep apnea was of the major complications in three patients. Bone fracture can be a presenting symptom, and in our patients it mainly occurred after the age of 3 years. Bone marrow suppression was seen in a single patient of our cohort who was misdiagnosed initially with malignant osteopetrosis. In this study, we also describe two novel (c.5G > A [p.Trp2Ter], c.538G > A [p.Gly180Ser]) and two reported (c.244-29 A > G, c.830C > T [p.Ala277Val]) CTSK mutations. Our results indicate that the recurrent intronic variant, c.244-29 A > G is likely to be a founder mutation, as it was found in 78% (14/18 patients) of our cohort belonging to the same tribe.

Expanding the phenome and variome of skeletal dysplasia.

PURPOSE: To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized. METHODS: Detailed phenotyping and next-generation sequencing (panel and exome). RESULTS: Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello-Carey syndrome-like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average. CONCLUSION: By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.

Clinical, Biochemical, and Molecular Features in 37 Saudi Patients with Very Long Chain Acyl CoA Dehydrogenase Deficiency.

BACKGROUND: Very long chain acyl CoA dehydrogenase (VLCAD) deficiency (OMIM#201475) is an autosomal recessive disorder of fatty acid beta oxidation caused by defect in the ACADVL. The aim of this study was to analyze the clinical, biochemical, and molecular features of VLCAD deficiency in Saudi Arabia, including the treatment and outcome. METHODS: We carried out a retrospective chart review analysis of 37 VLCAD deficiency patients from two tertiary centers in Saudi Arabia, over a 14-year period (2002-2016). Twenty-three patients were managed at King Abdul-Aziz Medical City and fourteen patients at King Fahad Medical City. RESULTS: Severe early onset VLCAD deficiency is the most frequent phenotype in our patients, caused by four different mutations in ACADVL; 31 patients (83.7%) had a homozygous nonsense mutation in exon 2 of ACADVL c.65C>A;p. Ser22X. Twenty-three patients died before the age of 2 years, despite early detection by newborn screening and implementation of treatment, including supplementation with medium chain triglycerides. CONCLUSION: This study reports the clinical, biochemical, molecular findings, treatment, and outcome of patients with VLCAD deficiency over the last 14 years. We identified the most common variant and one new variant in ACADVL. Despite early diagnosis and treatment, the outcome of VLCAD deficiency in this Saudi Arabian population remains poor. Preventive measures, such as prenatal diagnosis, could be implemented.