Jaberi-Elahi syndrome: Exploring a novel GTPBP2 mutation and a literature review.

Jaberi-Elahi syndrome is an extremely rare genetic disease caused by pathogenic variants in GTPBP2. The core symptoms of this disease are intellectual disability, motor development delay, abnormal reflexes, skeletal abnormalities, and visual impairment. In this study, we describe a three-year-old girl with a novel homozygous variant in GTPBP2 and a phenotype overlapping with Jaberi-Elahi syndrome. This variant (NM_019096.5:c.1289T > C, p.Leu430Pro) was identified by Whole Exome Sequencing and confirmed by Sanger sequencing although remains classified as VUS based on ACMG criteria. The proband demonstrated motor and intellectual developmental delay, muscle weakness, language disorder, facial dysmorphism, and poor growth. Hitherto, twenty-seven individuals with Jaberi-Elahi syndrome have been reported in the literature. This study, describes a review of the symptoms related to the Jaberi-Elahi syndrome. A large numbers of patients manifest motor development delay (26/28), sparse hair (26/28), and speech disorder (24/28). Moreover, a significant fraction of patients suffer from intellectual disability (23/28), hypotonia (23/28), skeletal problems (23/28), and visual impairment (18/28). In spite of previous patients, the proband in this study did not exhibit any skeletal abnormalities. In summary, we present evidence implicating a novel missense variant in Jaberi-Elahi syndrome, expanding and refining the genetic spectrum of this condition.

Two siblings with PEX11B-related peroxisome biogenesis disorder.

The PEX11ß gene contains four exons and encodes peroxisomal membrane protein 11ß, which is involved in peroxisome proliferation and division. Pathogenic variants in this gene result in a rare genetic disorder with autosomal recessive inheritance called peroxisome biogenesis disorder 14B (MIM: 614920). Here, we report two affected siblings with a novel variant (NM_003846: c.11G > A, p. Trp4Ter) in the PEX11ß gene that was identified by whole exome sequencing and confirmed by Sanger sequencing. The proband is a 22-year-old Iranian female who was born to consanguineous parents. The homozygous variant (NM_003846: c.11G > A, p. Trp4Ter) in the PEX11ß gene was identified in the proband, who presented with cataracts, strabismus, nystagmus, intellectual disability, developmental delay, speech disorders, dry skin, and behavioral problems. Her younger affected brother, who had the same homozygous variant, suffered from similar but slightly milder symptoms. This paper reports the seventh family in the world with novel pathogenic variants in the PEX11ß gene as the cause of peroxisome biogenesis disorder 14B. Additionally, the phenotypes of the previously reported patients are reviewed. Some of the phenotypes, such as bilateral congenital cataracts and intellectual disability, were present in all patients. However, other observed symptoms in previous cases, such as abnormal gait, myopia, abnormal muscle strength, hearing loss, gastrointestinal problems, skeletal disorders, and seizures, were not observed in the patients of this study. Further studies on this disorder could be valuable in determining the precise phenotype characteristics of this disease.

Novel insight into the phenotype of microcephaly 19 in the patient with missense COPB2 mutation.

COPB2 gene encodes the Coatomer Protein Complex Subunit Beta-2 that plays a crucial role in the cellular vesicle transport system and it is essential for brain development during embryogenesis. Mutations in COPB2 lead to an extremely rare genetic disease named Microcephaly type 19 with autosomal recessive inheritance. This study describes a missense pathogenic homozygous variant (NM_004766.3:c.760 C > T, p.Arg254Cys) in the COPB2 gene, which was identified by Whole-Exome sequencing and confirmed by Sanger sequencing. The proband of the present study is an eight-and-a-half-year-old Iranian female who was born to consanguineous parents. She manifests global developmental delay, intellectual disability, microcephaly, seizures, spasticity, strabismus, and failure to thrive symptoms. Moreover, she is unable to stand, walk, or speak. Here we report the second homozygous mutation (NM_004766.3:c.760 C > T, p.Arg254Cys) in the COPB2 gene in the second family in the world with MCPH19. The responsible variant (NM_004766.3:c.760 C > T, p.Arg254Cys) for the observed symptoms in the proband was identical to the identified variant in the previously reported Caucasian/Native American family. Sharing this extremely rare pathogenic variant in two families with different origins is an extraordinary event that could aid us to determine the phenotype of this disease more precisely. Eventually, we provide a case-based review of the clinical features and compared our findings to the previously reported family for a better understanding of the clinical presentation of Microcephaly type 19 disease.

EPS8 variant causes deafness, autosomal recessive 102 (DFNB102) and literature review.

Pathogenic variants in the EPS8 gene result in nonsyndromic hearing loss. This gene encodes the EPS8 protein in cochlear inner hair cells and performs critical roles in stimulating actin polymerization and bundling. Thus far, only four pathogenic variations in EPS8 have been described. In this study, we report the fifth pathogenic variant in the EPS8 gene in an Iranian patient with DFNB102. Furthermore, we review literature cases with EPS8 mutations.

Spastic paraplegia 51: phenotypic spectrum related to novel homozygous AP4E1 mutation.

AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a genetically diverse group of neurologic disorders defined by complex spastic paraplegia. Different forms of AP-4-associated HSP are classified by chromosomal locus or causative gene. Spastic paraplegia 51 (SPG51) is a neurodevelopmental condition that is caused by autosomal recessive mutations in the adaptor protein complex 4 complex subunit 1 (AP4E1) gene. Further, previous studies described an autosomal dominant mutation in the AP4E1 gene has also been linked to persistent stuttering. Here, we describe a patient from a consanguineous marriage who manifested severe intellectual disability (ID), absent speech, microcephaly, seizure, and movement disorders. Exome sequencing identified a novel homozygous frame-shift variant (NM_007347.5:c.3214_3215del, p.Leu1072AlafsTer10) in the AP4E1 gene, which was confirmed by Sanger sequencing. In this study, we also reviewed the phenotype of the former cases. Our findings added to the knowledge of little-studied homozygous AP4E1 mutation.

A combination of two novels homozygous FCSK variants cause disorder of glycosylation with defective fucosylation: New patient and literature review.

Pathogenic variants in FCSK cause Congenital Disorder of Glycosylation with Defective Fucosylation-2 (FCSK-CDG; MIM: 618,324). It is a rare autosomal recessive genetic disease caused by defects in the L-fucose kinase, which is necessary for the fucose salvage pathway. Herein, we report two novel variants in an Iranian patient, the fourth individual with FCSK-CDG described in the literature. Two homozygous variants in FCSK (rs376941268; NM_145059.3: c.379C > A, p. Leu127Met and rs543223292; NM_145059.3: c.394G > C, p. Asp132His) were identified in the proband. Sanger sequencing conducted on his unaffected parents revealed that they were heterozygous for the same variants. The proband, a four-and-a-half year old Iranian male born to consanguineous parents, manifested Intellectual disability, growth delay, ophthalmic abnormalities, seizures, speech disorder, and feeding difficulties.

Two novel Warburg micro syndrome 1 cases caused by pathogenic variants in RAB3GAP1.

In this study, we detected a novel pathogenic variant and a previously reported variant in RAB3GAP1 by whole-exome sequencing (NM_001172435.2: c.1552C>T, p.Gln518*; c.1471C>T, p.Arg491*). The first patient is a 3-year-old girl who presented with bilateral congenital cataracts, developmental delay, abnormal craniofacial features, drug-resistant constipation, and corpus callosum hypoplasia. The proband of the second family is a 13-year-old boy who suffers from developmental delay, quadriplegia, intellectual disability, abnormal craniofacial features, and corpus callosum hypoplasia.

A novel frameshift pathogenic variant in ST3GAL5 causing salt and pepper developmental regression syndrome (SPDRS): A case report.

GM3 synthase deficiency is associated with salt and pepper developmental regression syndrome (SPDRS), a rare genetic disorder. Herein, we report the first Iranian patient with SPDRS. We detected a novel pathogenic variant of ST3GAL5 (NM_003896.4: c.1030_1031del, p.Ile344Cysfs*11). The proband had intellectual disability (ID), failure to thrive, cerebral atrophy, microcephaly, and atonic seizures. The main future challenge proceeding from the results of this study is the prenatal detection of the newly discovered variant; the next step would involve further studies to elucidate the phenotypic spectrum of SPDRS and detect new variants that could cause symptoms ranging from mild to severe.