An exome-first approach to aid in the diagnosis of primary ciliary dyskinesia

Shamseldin, Hanan E.; Mogarri, Ibrahim; Alqwaiee, Mansour M; Alharbi‎, Abdulrahman; Baqais, Khaled; Alsaadi, Muslim M.; Alanzi, Talal; Alhashem, Amal; Saghier, Afaf; Ameen, Waleed; Ibrahim, Niema; Yang, Jason; Abdulwahab, Firdous; Hashem, Mais; Chivukula, Raghu R.; Alkuraya, Fowzan S.

doi:10.1007/s00439-020-02170-2

Cited by 19 publications

(31 citation statements)

References 29 publications

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“…The most common variant identified in our study was c.804_806delGAA (p.Lys268del) in the RSPH9 gene (observed in three different families). In a recent large cohort study conducted in Saudi Arabia, this variant was the most common, which accounted for 34% of families with molecularly confirmed PC, even though it depended on WES and our results were mainly through gene panels [ 14 ]. It is worth to mention that studies conducted in other Arab countries with different ancestries (Egypt and Tunisia) reported CCDC39 as the most commonly involved gene in their population [ 15 , 16 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular characteristics of primary ciliary dyskinesia

Alzaid¹,

Al-Mobaireek

Almannai³

et al. 2021

International Journal of Pediatrics and Adolescent Medicine

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Background Primary ciliary dyskinesia (PCD) is a ciliopathy with diverse clinical and genetic findings caused by abnormal motile cilia structure and function. In this study, we describe the clinical characteristics of confirmed PCD cases in our population and report the radiological, genetic, and laboratory findings. Methods This was a retrospective, observational, single-centre study. We enrolled 18 patients who were diagnosed with confirmed PCD between 2015 and 2019. We then analyzed their data, including clinical findings and workup. Results In our cohort, 56% of patients had molecularly confirmed PCD, and RSPH9 was the most common gene identified. Transmission electron microscopy (TEM) showed an ultrastructural defect in 64% of samples, all of which matched the genetic background of the patient. Situs inversus (SI) was observed in 50% of patients, and congenital heart disease was observed in 33%. The median body mass index (BMI) was 15.87 kg/m 2 , with a median z score of -1.48. The median FEV1 value was 67.6% (z score - 2.43). Radiologically, bronchiectasis was noted in 81% of patients at a variable degree of severity. Lung bases were involved in 91% of patients. We were unable to correlate the genotype-phenotype findings. Conclusion We describe the clinical and molecular characteristics of patients with confirmed PCD in a tertiary centre in Saudi Arabia and report 9 new pathogenic or likely pathogenic variants in one of the PCD-associated genes.

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Section: Discussionmentioning

confidence: 99%

Clinical and molecular characteristics of primary ciliary dyskinesia

Alzaid¹,

Al-Mobaireek

Almannai³

et al. 2021

International Journal of Pediatrics and Adolescent Medicine

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“…Very recently, a homozygous nonsense variant in AKNA has been reported in a family with a PCD-like phenotype [16], however, the authors did not show abnormally beating motile cilia, thus the chronic pulmonary infections and alteration of mucosal clearance with the PCD-like phenotype might be secondary due to other functions of ANKA in mucosal homoeostasis. The variant that they identified, NM_030767:c.1990C > T, p.(Gln664*), is predicted to result in a PTC in the AT-hook domain of AKNA and seems to interfere more prominently with the transcription factor function of AKNA rather than the regulation of microtubule organization during neurogenesis.…”

Section: Discussionmentioning

confidence: 90%

“…The microtubule organization protein AKNA was first described as KIAA1968, comprising a DNA-binding motif (called AT-hook) that specifically binds to AT-rich regions to regulate transcription of cellular immune response genes [13]. Reports on a knockout mouse model and truncating AKNA variants in dogs and humans have pointed to an inflammatory lung pathology or primary ciliary dyskinesia-like clinical picture with recurrent sinopulmonary infections as a major phenotypic consequence [14][15][16]. Recently, AKNA was found to have a role during prenatal stages of brain development in mice and in human cerebral organoids derived from human induced pluripotent stem cells (hiPSCs) [17].…”

Section: Introductionmentioning

confidence: 99%

A Homozygous AKNA Frameshift Variant Is Associated with Microcephaly in a Pakistani Family

Waseem

Moawia

Budde

et al. 2021

Genes

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Primary microcephaly (MCPH) is a prenatal condition of small brain size with a varying degree of intellectual disability. It is a heterogeneous genetic disorder with 28 associated genes reported so far. Most of these genes encode centrosomal proteins. Recently, AKNA was recognized as a novel centrosomal protein that regulates neurogenesis via microtubule organization, making AKNA a likely candidate gene for MCPH. Using linkage analysis and whole-exome sequencing, we found a frameshift variant in exon 12 of AKNA (NM_030767.4: c.2737delG) that cosegregates with microcephaly, mild intellectual disability and speech impairment in a consanguineous family from Pakistan. This variant is predicted to result in a protein with a truncated C-terminus (p.(Glu913Argfs*42)), which has been shown to be indispensable to AKNA’s localization to the centrosome and a normal brain development. Moreover, the amino acid sequence is altered from the beginning of the second of the two PEST domains, which are rich in proline (P), glutamic acid (E), serine (S), and threonine (T) and common to rapidly degraded proteins. An impaired function of the PEST domains may affect the intracellular half-life of the protein. Our genetic findings compellingly substantiate the predicted candidacy, based on its newly ascribed functional features, of the multifaceted protein AKNA for association with MCPH.

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“…LD is a complex disease, and its clinical phenotype presentations often overlap with PCD symptoms. A recent study from Saudi Arabia reported the overlapping clinical symptoms between PCD and LD patients ( 26 ). This report investigated a total of 81 patients, including 58 patients with sinopulmonary infections (SPIs), 15 patients with combined LD with SPIs, and six patients with LD alone.…”

Section: Discussionmentioning

confidence: 99%

Novel MYO1D Missense Variant Identified Through Whole Exome Sequencing and Computational Biology Analysis Expands the Spectrum of Causal Genes of Laterality Defects

et al. 2021

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Laterality defects (LDs) or asymmetrically positioned organs are a group of rare developmental disorders caused by environmental and/or genetic factors. However, the exact molecular pathophysiology of LD is not yet fully characterised. In this context, studying Arab population presents an ideal opportunity to discover the novel molecular basis of diseases owing to the high rate of consanguinity and genetic disorders. Therefore, in the present study, we studied the molecular basis of LD in Arab patients, using next-generation sequencing method. We discovered an extremely rare novel missense variant in MYO1D gene (Pro765Ser) presenting with visceral heterotaxy and left isomerism with polysplenia syndrome. The proband in this index family has inherited this homozygous variant from her heterozygous parents following the autosomal recessive pattern. This is the first report to show MYO1D genetic variant causing left–right axis defects in humans, besides previous known evidence from zebrafish, frog and Drosophila models. Moreover, our multilevel bioinformatics-based structural (protein variant structural modelling, divergence, and stability) analysis has suggested that Ser765 causes minor structural drifts and stability changes, potentially affecting the biophysical and functional properties of MYO1D protein like calmodulin binding and microfilament motor activities. Functional bioinformatics analysis has shown that MYO1D is ubiquitously expressed across several human tissues and is reported to induce severe phenotypes in knockout mouse models. In conclusion, our findings show the expanded genetic spectrum of LD, which could potentially pave way for the novel drug target identification and development of personalised medicine for high-risk families.

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An exome-first approach to aid in the diagnosis of primary ciliary dyskinesia

Cited by 19 publications

References 29 publications

Clinical and molecular characteristics of primary ciliary dyskinesia

Clinical and molecular characteristics of primary ciliary dyskinesia

A Homozygous AKNA Frameshift Variant Is Associated with Microcephaly in a Pakistani Family

Novel MYO1D Missense Variant Identified Through Whole Exome Sequencing and Computational Biology Analysis Expands the Spectrum of Causal Genes of Laterality Defects

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