NGS-driven molecular diagnosis of heterogeneous hereditary neurological disorders reveals novel and known variants in disease-causing genes

Khan, Ayaz; Tian, Shixiong; Tariq, Muhammad; Khan, Sheraz; Safeer, Muhammad; Ullah, Naimat; Akbar, Nazia; Javed, Iram; Asif, Muhammad; Ahmad, Ilyas; Ullah, Shahid; Satti, Humayoon Shafique; Khan, Raees Ahmad; Naeem, Muhammad; Ali, Muzzammil; Rendu, John; Fauré, Julien; Dieterich, Klaus; Latypova, Xénia; Baig, Shahid Mahmood; Malik, Naveed Altaf; Zhang, Feng; Khan, Tahir Naeem; Liu, Chunyu

doi:10.1007/s00438-022-01945-8

Cited by 3 publications

(3 citation statements)

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“…In our study, we identified four novel pathogenic variants in ZFYVE26, SACS, BICD2, and B4GALNT1, two ALS2 variants of uncertain significance (VUS) in six unrelated consanguineous families (Family A-F), and three previously reported variants in FA2H, APTX, and SETX in Families G-I [17][18][19][20]. The ALS2 VUS are considered as the underlying cause of the disease because the phenotypic features observed in our patients are consistent with the ALS2-related disease, but further functional analysis is required to prove the possible pathogenicity.…”

Section: Discussionmentioning

confidence: 81%

“…Data analysis of Families G, H, and I revealed previously reported variants FA2H: c.159_176del (p.53_58del), APTX: c.689T>G (p.Val230Gly), and SETX: c.5308_5311del (p.Glu1770fs), respectively [17][18][19][20] (Figures Figure 2 and S3). According to ACMG guidelines, all variants are classified as either pathogenic or likely pathogenic except the ALS2 variants, which are classified as variants of uncertain significance (VUS).…”

Section: Molecular Findingsmentioning

confidence: 73%

“…FA2H encodes for the lipid biosynthetic enzyme fatty acid 2-hydroxylase, which is involved in the formation of the brain cell's myelin sheath which protects the neuronal axons from damage and enhances the nerve conduction rate [38]. Recently, three Pakistani families reported the same variant (FA2H: c.159_176del), hence classifying it as a founder effect mutation in the Pakistani population [18].…”

Section: Discussionmentioning

confidence: 99%

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Genetic Investigation of Consanguineous Pakistani Families Segregating Rare Spinocerebellar Disorders

Saadi,

Cali,

Khalid

et al. 2023

Genes

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Spinocerebellar disorders are a vast group of rare neurogenetic conditions, generally characterized by overlapping clinical symptoms including progressive cerebellar ataxia, spastic paraparesis, cognitive deficiencies, skeletal/muscular and ocular abnormalities. The objective of the present study is to identify the underlying genetic causes of the rare spinocerebellar disorders in the Pakistani population. Herein, nine consanguineous families presenting different spinocerebellar phenotypes have been investigated using whole exome sequencing. Sanger sequencing was performed for segregation analysis in all the available individuals of each family. The molecular analysis of these families identified six novel pathogenic/likely pathogenic variants; ZFYVE26: c.1093del, SACS: c.1201C>T, BICD2: c.2156A>T, ALS2: c.2171-3T>G, ALS2: c.3145T>A, and B4GALNT1: c.334_335dup, and three already reported pathogenic variants; FA2H: c.159_176del, APTX: c.689T>G, and SETX: c.5308_5311del. The clinical features of all patients in each family are concurrent with the already reported cases. Hence, the current study expands the mutation spectrum of rare spinocerebellar disorders and implies the usefulness of next-generation sequencing in combination with clinical investigation for better diagnosis of these overlapping phenotypes.

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Section: Discussionmentioning

confidence: 81%

Section: Molecular Findingsmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

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Genetic Investigation of Consanguineous Pakistani Families Segregating Rare Spinocerebellar Disorders

Saadi,

Cali,

Khalid

et al. 2023

Genes

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New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN

Monteil,

Guérineau,

Gil-Nagel

et al. 2024

Physiological Reviews

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Cell excitability and its modulation by hormones and neurotransmitters involve the concerted action of membrane proteins, especially ion channels. Unique complements of co-expressed ion channels are exquisitely balanced against each other in different excitable cell types, establishing distinct electrical properties that are tailored for diverse physiological contributions, and dysfunction of any component may induce a disease state. A crucial parameter controlling cell excitability is the resting membrane potential (RMP) set by extra- and intra-cellular concentrations of ions, mainly Na+, K+, and Cl-, and their passive permeation across the cell membrane through leak ion channels. Indeed, dysregulation of RMP causes significant effects on cellular excitability. This review describes the molecular and physiological properties of the Na+ leak channel NALCN, which associates with its accessory subunits UNC-79, UNC-80, and NLF-1/FAM155 to conduct depolarizing background Na+ currents in various excitable cell types, especially neurons. Studies of animal models clearly demonstrate that NALCN contributes to fundamental physiological processes in the nervous system including the control of respiratory rhythm, circadian rhythm, sleep and locomotor behavior. Furthermore, dysfunction of NALCN and its subunits is associated with severe pathological states in humans. The critical involvement of NALCN in physiology is now well established, but its study has been hampered by the lack of specific drugs that can block or agonize NALCN currents in vitro and in vivo. Molecular tools and animal models are now available to accelerate our understanding of how NALCN contributes to key physiological functions, and the development of novel therapies for NALCN channelopathies.

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Widening the infantile hypotonia with psychomotor retardation and characteristic Facies-1 Syndrome’s clinical and molecular spectrum through NALCN in-silico structural analysis

Vecchio,

Macchiaiolo,

Gonfiantini

et al. 2024

Front. Genet.

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IntroductionInfantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1, MIM#615419) is a rare, birth onset, autosomal recessive disorder caused by homozygous or compound heterozygous truncating variants in NALCN gene (MIM#611549) resulting in a loss-of-function effect.MethodsWe enrolled a new IHPRF1 patients’ cohort in the framework of an international multicentric collaboration study. Using specialized in silico pathogenicity predictors and ad hoc structural analyses, we assessed the mechanistic consequences of the deleterious variants retrieved on NALCN structure and function.ResultsTo date 38 different NALCN variants have been retrieved from 33 different families, 26 from unrelated and 22 from related patients. We report on five new IHPRF1 patients from four different families, harboring four newly identified and one previously retrieved variant that exhibited a markedly significant functional impact, thereby compromising the functionality of the protein complex.DiscussionBy widening the functional spectrum of biallelic variants affecting the NALCN gene, this article broadens the IHPRF1 syndrome’s genotype-phenotype correlation and gives new insight into its pathogenic mechanism, diagnosis, and clinical management.

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NGS-driven molecular diagnosis of heterogeneous hereditary neurological disorders reveals novel and known variants in disease-causing genes

Cited by 3 publications

References 55 publications

Genetic Investigation of Consanguineous Pakistani Families Segregating Rare Spinocerebellar Disorders

Genetic Investigation of Consanguineous Pakistani Families Segregating Rare Spinocerebellar Disorders

New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN

Widening the infantile hypotonia with psychomotor retardation and characteristic Facies-1 Syndrome’s clinical and molecular spectrum through NALCN in-silico structural analysis

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