Further delineation of the phenotypic spectrum of ISCA2 defect: A report of ten new cases

Iron-Sulfur Cluster (ISC) biogenesis is a vital cellular process required to produce various ISC-containing proteins. These ISC proteins are responsible for essential functions such as glycine cleavage and the formation of lipoic acid, an essential cofactor of respiratory chain complexes. Defects in ISC biogenesis lead to multiple mitochondrial dysfunction syndromes including: ISCA2 with infantile onset leukodystrophy. Recently, a founder mutation, c.229G > A, p.Gly77Ser in ISCA2 was reported to cause Multiple Mitochondrial Dysfunction Syndrome type 4. In a retrospective review of children diagnosed with the ISCA2 defect, we were able to identify ten new patients who were not reported previously with the identical founder mutation. High CSF glycine levels and elevated glycine peaks on MR spectroscopy were demonstrated in all tested probands. All patients were between 3 and 7 months of age with a triad of neurodevelopmental regression, nystagmus and optic atrophy and leukodystrophy. MRI findings were typical in the patients with diffuse, abnormal white matter signal in the cerebrum, cerebellum, brain stem and spinal cord. The patients ended up in a vegetative state, and often premature death due to respiratory infections. We alert clinicians to consider the ISCA2 defect as a differential diagnosis of infantile onset leukodystrophies affecting the brain as well as the spinal cord, especially in the presence of elevated CSF glycine or elevated glycine peaks in MR spectroscopy

A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families

The genetic architecture of mitochondrial disease continues to expand and currently exceeds more than 350 disease-causing genes. Bi-allelic variants in RTN4IP1, also known as Optic Atrophy-10 (OPA10), lead to early-onset recessive optic neuropathy, atrophy, and encephalopathy in the afflicted patients. The gene is known to encode a mitochondrial ubiquinol oxidoreductase that interacts with reticulon 4 and is thought to be a mitochondrial antioxidant NADPH oxidoreductase. Here, we describe two unrelated consanguineous families from the northern region of Saudi Arabia harboring a missense variant (RTN4IP1:NM_032730.5; c.475G<T, p.Val159Phe) in the gene. Clinically affected individuals presented with intellectual disability, encephalopathy, ataxia, optic atrophy, and seizures. Based on whole exome sequencing and confirmatory Sanger sequencing, the variant was fully segregated with the phenotype in the families, absent among large ethnically matching controls as well as numerous in-house exomes, and predicted to be pathogenic by different in silico classifiers. Structural modeling and immunoblot analyses strongly indicated this variant to be pathogenic. Since the families belong to one of the tribal inhabitants of Saudi Arabia, we postulate that the variant is likely to be a founder. We provide the estimated age of the variant and present data confirming the disease-causality of this founder variant

Identification of novel genomic imbalances in Saudi patients with congenital heart disease

Abstract Background Quick genetic diagnosis of a patient with congenital heart disease (CHD) is quite important for proper health care and management. Copy number variations (CNV), chromosomal imbalances and rearrangements have been frequently associated with CHD. Previously, due to limitations of microscope based standard karyotyping techniques copious CNVs and submicroscopic imbalances could not be detected in numerous CHD patients. The aim of our study is to identify cytogenetic abnormalities among the selected CHD cases (n = 17) of the cohort using high density oligo arrays. Results Our screening study indicated that six patients (~35%) have various cytogenetic abnormalities. Among the patients, only patient 2 had a duplication whereas the rest carried various deletions. The patients 1, 4 and 6 have only single large deletions throughout their genome; a 3.2 Mb deletion on chromosome 7, a 3.35 Mb deletion on chromosome 3, and a 2.78 Mb a deletion on chromosome 2, respectively. Patients 3 and 5 have two deletions on different chromosomes. Patient 3 has deletions on chromosome 2 (2q24.1; 249 kb) and 16 (16q22.2; 1.8 Mb). Patient 4 has a 3.35 Mb an interstitial deletion on chromosome 3 (3q13.2q13.31). Based on our search on the latest available literature, our study is the first inclusive array CGH evaluation on Saudi cohort of CHD patients. Conclusions This study emphasizes the importance of the arrays in genetic diagnosis of CHD. Based on our results the high resolution arrays should be utilized as first-tier diagnostic tool in clinical care as suggested before by others. Moreover, previously evaluated negative CHD cases (based on standard karyotyping methods) should be re-examined by microarray based cytogenetic methods

Clinical and genetic characteristics of 15 families with hereditary hypophosphatemia:Novel Mutations in PHEX and SLC34A3

Hereditary hypophosphatemia is a group of rare renal phosphate wasting disorders. The diagnosis is based on clinical, radiological, and biochemical features, and may require genetic testing to be confirmed.Clinical features and mutation spectrum were investigated in patients with hereditary hypophosphatemia. Genomic DNA of 23 patients from 15 unrelated families were screened sequentially by PCR-sequencing analysis for mutations in the following genes: PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1. CytoScan HD Array was used to identify large deletions.Genetic evaluation resulted in the identification of an additional asymptomatic but intermittent hypophosphatemic subject. Mutations were detected in 21 patients and an asymptomatic sibling from 13 families (86.6%, 13/15). PHEX mutations were identified in 20 patients from 12 families. Six of them were novel mutations present in 9 patients: c.983_987dupCTACC, c.1586+2T>G, c.1206delA, c.436+1G>T, c.1217G>T, and g.22,215,887-22,395,767del (179880 bp deletion including exon 16-22 and ZNF645). Six previously reported mutations were found in 11 patients. Among 12 different PHEX mutations, 6 were de novo mutations. Patients with de novo PHEX mutations often had delayed diagnosis and significantly shorter in height than those who had inherited PHEX mutations. Novel compound heterozygous mutations in SLC34A3 were found in one patient and his asymptomatic sister: c.1335+2T>A and c.1639_1652del14. No mutation was detected in two families.This is the largest familial study on Turkish patients with hereditary hypophosphatemia. PHEX mutations, including various novel and de novo variants, are the most common genetic defect. More attention should be paid to hypophosphatemia by clinicians since some cases remain undiagnosed both during childhood and adulthood

Clinical and laboratory characteristics of children with de novo or inherited <i>PHEX</i> mutations.

<p>Clinical and laboratory characteristics of children with de novo or inherited <i>PHEX</i> mutations.</p

<i>In silico</i> prediction of single nucleotide variations in the <i>PHEX</i> gene.

<p><i>In silico</i> prediction of single nucleotide variations in the <i>PHEX</i> gene.</p

Characterization of a large deletion of <i>PHEX</i> in patient V-3.

<p>(A) Genechip cytogenetics array results. The top is showing weighted log2 ratios plot showing a normal copy number state for the X chromosome. The deletion is indicated by a dark bar and enclosed in the black lines. More than 70 SNP probes are present in the deleted region and indicated by an arrow. (B) Schematic representation of 179,880 bp deletion of <i>PHEX</i> and <i>ZNF645</i>. The 5’ breakpoint is located in the intron 15 of <i>PHEX</i> and 7 kb from exon 15. The 3’ breakpoint point is 103 kb from <i>ZNF645</i>, resulting in the deletion of exon 16–22 of PHEX and entire <i>ZNF645</i>. The 5’ and 3’ undeleted nucleotide sequences are highlightted in bold. Deletion analysis is based on GRCh37/hg19. (C) Electropherogram of the breaking point. The DNA fragment was amplified by PCR using primers flanking the 5’ and 3’ deletion point. The breakpoint is indicated by an arrow.</p

Summary of clinical and laboratory findings in patients with hereditary hypophosphatemia.

<p>Summary of clinical and laboratory findings in patients with hereditary hypophosphatemia.</p

Sequence analysis of <i>PHEX</i> in patients with hereditary hypophosphatemia.

<p>(A) Five novel <i>PHEX</i> mutations. c.983_987dupCTACC (patient II-3 and her mother) and c.436+1G>T (patient IX-3 and his mother) are inherited mutations from mother; c.1586+2T>G (patinet IV-3), c.1206delA (patient XV-3), and c.1217G>T (patientVI-3) are de novo mutations not present in parents. The c.1586+2T>G results in exon 14 skipping. (B) Six previously reported <i>PHEX</i> mutations. c.1645C>T, c. 187+1G>T, and c.2104C>T are de novo mutations. c.1601C>T, c.2239C>T, and c.1404+1del G are inherited mutations transmitted from mother. Mutation is indicated by an arrow.</p

Sequence analysis of <i>SLC34A3</i> in a patient with hereditary hypophosphatemia.

<p>A novel heterozygous mutation c.1639-1652del14 is present in the mother, patient, and his sister. A novel heterozygous splice donor site mutation c.1335+2T>A is present in the father, patient, and his sister. Compound heterozygous <i>SLC34A3</i> mutations are carried by both patient and his sister. Mutation is indicated by an arrow.</p