Polycystic ovary syndrome (PCOS) is a common infertility disorder affecting a significant proportion of the global population. It is the main cause of anovulatory infertility in women and is the most ...common endocrinopathy affecting reproductive-aged women, with a prevalence of 8-13% depending on the criteria used and population studied. The disease is multifactorial and complex and, therefore, often difficult to diagnose due to overlapping symptoms. Multiple etiological factors have been implicated in PCOS. Due to the complex pathophysiology involving multiple pathways and proteins, single genetic diagnostic tests cannot be determined. Progress has been achieved in the management and diagnosis of PCOS; however, not much is known about the molecular players and signaling pathways underlying it. Conclusively PCOS is a polygenic and multifactorial syndromic disorder. Many genes have been associated with PCOS, which affect fertility either directly or indirectly. However, studies conducted on PCOS patients from multiple families failed to find a fully penetrant variant(s). The present study was designed to review the current genetic understanding of the disease. In the present review, we have discussed the clinical spectrum, the genetics, and the variants identified as being associated with PCOS. The mechanisms by which variants in the genes confer risk to PCOS and the nature of the physical and genetic interaction between the genetic elements underlying PCOS remain to be determined. Elucidation of genetic players and cellular pathways underlying PCOS will certainly increase our understanding of the pathophysiology of this syndrome. The study also discusses the current status of the treatment modalities for PCOS, which is important to find new ways of treatment.
The aim of this study was to identify the underlying genetic defect in a family segregating autosomal recessive asymmetric hereditary motor neuropathy (HMN). Asymmetric HMN has not been associated ...earlier with SORD mutations.
For this study, we have recruited a family and collected blood samples from affected and normal individuals of a family. Detailed clinical examination and electrophysiological studies were carried out. Whole exome sequencing was performed to detect the underlying genetic defect in this family. The potential variant was validated using the Sanger sequencing approach.
Clinical and electrophysiological examination revealed asymmetric motor neuropathy with normal nerve conduction velocities and action potentials. Genetic analysis identified a homozygous mononucleotide deletion mutation (c.757delG) in a SORD gene in a patient. This mutation is predicted to cause premature truncation of a protein (p.A253Qfs*27).
Interestingly, the patient with homozygous SORD mutation demonstrates normal motor and nerve conduction velocities and action potentials. The affected individual describes in this study has a unique presentation of asymmetric motor neuropathy predominantly affecting the right side more than the left as supported by the clinical examination. This is the first report of SORD mutation from Saudi Arabia and this study further expands the phenotypic spectrum of SORD mutation.
Autism spectrum disorder (ASD) is a complicated, lifelong neurodevelopmental disorder affecting verbal and non-verbal communication and social interactions. ASD signs and symptoms appear early in ...development before the age of 3 years. It is unlikely for a person to acquire autism after a period of normal development. However, we encountered an 8-year-old child who developed ASD later in life although his developmental milestones were normal at the beginning of life. Sequencing the complete coding part of the genome identified a hemizygous nonsense mutation (NM_001367857.2):c.1803C>G; (p.Tyr601Ter) in the gene (SATL1) encoding spermidine/spermine N1-acetyl transferase like 1. Screening an ASD cohort of 28 isolated patients for the SATL1 gene identified another patient with the same variant. Although SATL1 mutations have not been associated with any human diseases, our data suggests that a mutation in SATL1 is the underlying cause of ASD in our cases. In mammals, mutations in spermine synthase (SMS), an enzyme needed for the synthesis of spermidine polyamine, have been reported in a syndromic form of the X-linked mental retardation. Moreover, SATL1 gene expression studies showed a relatively higher expression of SATL1 transcripts in ASD related parts of the brain including the cerebellum, amygdala and frontal cortex. Additionally, spermidine has been characterized in the context of learning and memory and supplementations with spermidine increase neuroprotective effects and decrease age-induced memory impairment. Furthermore, spermidine biosynthesis is required for spontaneous axonal regeneration and prevents α-synuclein neurotoxicity in invertebrate models. Thus, we report, for the first time, that a mutation in the SATL1 gene could be a contributing factor in the development of autistic symptoms in our patients.
We performed whole exome sequencing to identify an unknown genetic cause of azoospermia and male infertility in a large Pakistani family. Three infertile males were subjected to semen analysis, ...hormone testing, testicular histology, ultrasonography, karyotyping, Y-chromosome microdeletion and CFTR testing. The clinical testing suggested a diagnosis of obstructive azoospermia (OA). To identify the cause, we performed whole exome sequencing (WES) for 2 infertile brothers and 2 fertile family members. For segregation analysis and variant confirmation, we performed Sanger sequencing. WES data analysis of the family revealed segregated variants in 3 candidate genes. We considered novel nonsense variant c.2440C > T(p.Arg814*) in X-linked gene ADGRG2 as biologically most plausible. It is predicted to truncate the protein by 204 amino acids (aa) at a key transmembrane domain. Adgrg2-knockout male mice show sperm loss due to obstructive fluid stasis, while ADGRG2 mutations cause OA in the infertile male patients. Our analysis of testicular histology reveals secondary severe reduction of spermatogenesis, consistent with human and knockout mouse phenotypes. The ADGRG2 nonsense mutation is absent in the largest population databases, ExAC and gnomAD. Analysis of the novel nonsense mutation in extended family members confirmed co-segregation of the mutation with OA in all affected males. The likely pathogenic nature of the mutation is supported by its truncation effect on the transmembrane domain and distinctive ultrasound results. The study demonstrates effectiveness of WES in discovering a genetic cause of azoospermia.
Congenital hearing impairment (HI) is genetically heterogeneous making its genetic diagnosis challenging. Investigation of novel HI genes and variants will enhance our understanding of the molecular ...mechanisms and to aid genetic diagnosis. We performed exome sequencing and analysis using DNA samples from affected members of two large families from Ghana and Pakistan, segregating autosomal-dominant (AD) non-syndromic HI (NSHI). Using in silico approaches, we modeled and evaluated the effect of the likely pathogenic variants on protein structure and function. We identified two likely pathogenic variants in SLC12A2, c.2935G>A:p.(E979K) and c.2939A>T:p.(E980V), which segregate with NSHI in a Ghanaian and Pakistani family, respectively. SLC12A2 encodes an ion transporter crucial in the homeostasis of the inner ear endolymph and has recently been reported to be implicated in syndromic and non-syndromic HI. Both variants were mapped to alternatively spliced exon 21 of the SLC12A2 gene. Exon 21 encodes for 17 residues in the cytoplasmatic tail of SLC12A2, is highly conserved between species, and preferentially expressed in cochlear tissues. A review of previous studies and our current data showed that out of ten families with either AD non-syndromic or syndromic HI, eight (80%) had variants within the 17 amino acid residue region of exon 21 (48 bp), suggesting that this alternate domain is critical to the transporter activity in the inner ear. The genotypic spectrum of SLC12A2 was expanded and the involvement of SLC12A2 in ADNSHI was confirmed. These results also demonstrate the role that SLC12A2 plays in ADNSHI in diverse populations including sub-Saharan Africans.
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy characterized by epileptic seizures, macrocephaly, and vacuolization of myelin and astrocyte. The ...magnetic resonance imaging of the brain of MLC patients shows diffuse white-matter anomalies and the occurrence of subcortical cysts. MLC features have been observed in individuals having mutations in the MLC1 or HEPACAM genes. In this study, we recruited a six generation large kindred with five affected individuals manifesting clinical features of epileptic seizures, macrocephaly, ataxia, and spasticity. In order to identify the underlying genetic cause of the clinical features, we performed whole-genome genotyping using Illumina microarray followed by detection of loss of heterozygosity (LOHs) regions. One affected individual was exome sequenced as well. Homozygosity mapping detected several LOH regions due to extensive consanguinity. An unbiased and hypothesis-free exome data analysis identified a homozygous missense variant (NM_015166.3:c.278C>T) in the exon 4 of the MLC1 gene. The variant is present in the LOH region on chromosome 22q (50 Mb) and segregates perfectly with the disorder within the family in an autosomal recessive manner. The variant is present in a highly conserved first cytoplasmic domain of the MLC1 protein (NM_015166.3:p.(Ser93Leu)). Interestingly, heterozygous individuals show seizure and mild motor function deterioration. We propose that the heterozygous variant in MLC1 might disrupt the functional interaction of MLC1 with GlialCAM resulting in mild clinical features in carriers of the variant.
Sensorineural hearing loss is genetically heterogeneous. Here, we report that mutations in CIB2, which encodes a calcium- and integrin-binding protein, are associated with nonsyndromic deafness ...(DFNB48) and Usher syndrome type 1J (USH1J). One mutation in CIB2 is a prevalent cause of deafness DFNB48 in Pakistan; other CIB2 mutations contribute to deafness elsewhere in the world. In mice, CIB2 is localized to the mechanosensory stereocilia of inner ear hair cells and to retinal photoreceptor and pigmented epithelium cells. Consistent with molecular modeling predictions of calcium binding, CIB2 significantly decreased the ATP-induced calcium responses in heterologous cells, whereas mutations in deafness DFNB48 altered CIB2 effects on calcium responses. Furthermore, in zebrafish and Drosophila melanogaster, CIB2 is essential for the function and proper development of hair cells and retinal photoreceptor cells. We also show that CIB2 is a new member of the vertebrate Usher interactome.
Summary
Background
Hereditary hypertrichosis (HH) is characterized by excessive hair growth on various body areas, which is independent of the individual's age. This rare hair disorder has been ...classified by its origin (genetic or acquired), age of onset, breadth of hair distribution (universal or localized) and the affected body areas. HH is often linked to several additional congenital abnormalities involving teeth, heart and bones. Human HH is associated with heterozygous genomic duplications and deletions in the chromosomal region 17q24.2–q24.3, containing genes such as ABCA5, ABCA6, ABCA10 and MAP2K6. Recently, a homozygous splice‐site variant in ABCA5 has been reported to cause autosomal recessive congenital generalized hypertrichosis terminalis (CGHT; OMIM 135400).
Aim
To investigate the clinical and genetic basis of autosomal recessive hypertrichosis in a large consanguineous Pakistani family.
Methods
In the present study, we characterized a family of Pakistani origin segregating CGHT in an autosomal recessive pattern, using whole exome sequencing followed by Sanger sequencing
Results
We identified a novel 2‐bp intragenic deletion NM_172232.4(ABCA5);c.977_978delAT causing a frameshift variant (p.His326ArgfsTer5) in ABCA5.
Conclusions
To our knowledge, this is the first intragenic deletion in ABCA5 underlying CGHT. The findings further validate the involvement of ABCA5 in hair development. The study will facilitate genetic counselling of families carrying CGHT‐related features in Pakistani and other populations.
It is known that a splice‐site variant in the ABCA5 gene results in autosomal recessive hypertrichosis. We have identified the first intragenic deletion and second intragenic variant in ABCA5, underlying the congenital generalized hypertrichosis terminalis disorder. Moreover, we showed that the mRNA is absent in the patient's hair follicle as a result of this variant. This finding of the first intragenic deletion in ABCA5, identified in the present study, validates the involvement of the ABCA5 in hair development.
Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to 2
-generation ALK inhibitors. Lorlatinib (PF-06463922) (6) is a 3
...-generation macrocyclic ALK-TKI that demonstrates many advantages over 2
-generation ALK inhibitors. Lorlatinib has demonstrated decent kinase selectivity, promising pharmacokinetic profile, selective brain-penetration and strong antiproliferative activity in several ALK/ROS1-driven tumor models. The current review describes the activity spectrum, key events from discovery to clinical applications and the evidences that lorlatinib acts as an ALK/ROS1 inhibitor in clinical settings.
Primary failure of tooth eruption (PFE) is a rare odontogenic defect and is characterized by failure of eruption of one or more permanent teeth. The aim of the study is to identify the genetic defect ...in a family with seven affected individuals segregating autosomal dominant non-syndromic PFE. Whole genome single-nucleotide polymorphism (SNP) genotyping was performed. SNP genotypes were analysed by DominantMapper and multiple shared haplotypes were detected on different chromosomes. Four individuals, including three affected, were exome sequenced. Variants were annotated and data were analysed while considering candidate chromosomal regions. Initial analysis of variants obtained by whole exome sequencing identified damaging variants in C15orf40, EPB41L4A, TMEM232, KMT2C, and FBXW10 genes. Sanger sequencing of all family members confirmed segregation of splice acceptor site variant (c.1013-2 A > G) in the KMT2C gene with the phenotype. KMT2C is considered as a potential candidate gene based on segregation analysis, the absence of variant in the variation databases, the presence of variant in the shared identical by descent (IBD) region and in silico pathogenicity prediction. KMT2C is a histone methyltransferase and recently the role of another member of this family (KMT2D) has been implicated in tooth development. Moreover, protein structures of KMT2C and KMT2D are highly similar. In conclusion, we have identified that the KMT2C gene mutation causes familial non-syndromic PFE. These findings suggest the involvement of KMT2C in the physiological eruption of permanent teeth.
PDF
