Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations, Hypomyelination, and Arthrogryposis

Leukodystrophies and genetic leukoencephalopathies are a heterogeneous group of heritable disorders that affect the glial-axonal unit. As more patients with unsolved leukodystrophies and genetic leukoencephalopathies undergo next generation sequencing, causative mutations in genes leading to central hypomyelination are being identified. Two such individuals presented with arthrogryposis multiplex congenita, congenital hypomyelinating neuropathy, and central hypomyelination with early respiratory failure. Whole exome sequencing identified biallelic mutations in the CNTNAP1 gene: homozygous c.1163G>C (p.Arg388Pro) and compound heterozygous c.967T>C (p.Cys323Arg) and c.319C>T (p.Arg107*). Sural nerve and quadriceps muscle biopsies demonstrated progressive, severe onion bulb and axonal pathology. By ultrastructural evaluation, septate axoglial paranodal junctions were absent from nodes of Ranvier. Serial brain magnetic resonance images revealed hypomyelination, progressive atrophy, and reduced diffusion in the globus pallidus in both patients. These 2 families illustrate severe progressive peripheral demyelinating neuropathy due to the absence of septate paranodal junctions and central hypomyelination with neurodegeneration in CNTNAP1-associated arthrogryposis multiplex congenita.

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CNTNAP1 mutations cause CNS hypomyelination and neuropathy with or without arthrogryposis

Neurology Genetics ◽

10.1212/nxg.0000000000000144 ◽

2017 ◽

Vol 3 (2) ◽

pp. e144 ◽

Cited By ~ 15

Author(s):

Holger Hengel ◽

Alex Magee ◽

Muhammad Mahanjah ◽

Jean-Michel Vallat ◽

Robert Ouvrier ◽

...

Keyword(s):

Brain Mri ◽

Cerebellar Atrophy ◽

Nerve Biopsy ◽

Compound Heterozygous ◽

Arthrogryposis Multiplex Congenita ◽

Whole Exome ◽

Paranodal Junctions ◽

Distinct Features ◽

Deep Phenotyping

Objective:To explore the phenotypic spectrum and pathophysiology of human disease deriving from mutations in the CNTNAP1 gene.Methods:In a field study on consanguineous Palestinian families, we identified 3 patients carrying homozygous mutations in the CNTNAP1 gene using whole-exome sequencing. An unrelated Irish family was detected by screening the GENESIS database for further CNTNAP1 mutations. Neurophysiology, MRI, and nerve biopsy including electron microscopy were performed for deep phenotyping.Results:We identified 3 novel CNTNAP1 mutations in 5 patients from 2 families: c.2015G>A:p.(Trp672*) in a homozygous state in family 1 and c.2011C>T:p.(Gln671*) in a compound heterozygous state with c.2290C>T:p.(Arg764Cys) in family 2. Affected patients suffered from a severe CNS disorder with hypomyelinating leukodystrophy and peripheral neuropathy of sensory-motor type. Arthrogryposis was present in 2 patients but absent in 3 patients. Brain MRI demonstrated severe hypomyelination and secondary cerebral and cerebellar atrophy as well as a mega cisterna magna and corpus callosum hypoplasia. Nerve biopsy revealed very distinct features with lack of transverse bands at the paranodes and widened paranodal junctional gaps.Conclusions:CNTNAP1 mutations have recently been linked to patients with arthrogryposis multiplex congenita. However, we show that arthrogryposis is not an obligate feature. CNTNAP1-related disorders are foremost severe hypomyelinating disorders of the CNS and the peripheral nervous system. The pathology is partly explained by the involvement of CNTNAP1 in the proper formation and preservation of paranodal junctions and partly by the assumed role of CNTNAP1 as a key regulator in the development of the cerebral cortex.

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Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106031 ◽

2019 ◽

Vol 56 (11) ◽

pp. 750-757 ◽

Cited By ~ 11

Author(s):

Weili Wang ◽

Chaofeng Tu ◽

Hongchuan Nie ◽

Lanlan Meng ◽

Yong Li ◽

...

Keyword(s):

Sperm Morphology ◽

Mutation Screening ◽

Compound Heterozygous ◽

Obstructive Azoospermia ◽

Control Cohort ◽

Chinese Families ◽

Whole Exome ◽

Compound Heterozygous Mutations ◽

Biallelic Mutations ◽

Immotile Spermatozoa

BackgroundThe genetic causes for most male infertility due to severe asthenozoospermia remain unclear.ObjectiveOur objective was to identify unknown genetic factors in 47 patients with severe asthenozoospermia from 45 unrelated Chinese families.MethodsWe performed whole exome sequencing of 47 individuals with severe asthenozoospermia from 45 unrelated families. Mutation screening was performed in a control cohort of 637 individuals, including 219 with oligoasthenospermia, 195 with non-obstructive azoospermia and 223 fertile controls. Ultrastructural and immunostaining analyses of patients’ spermatozoa were performed to characterise the effect of variants.ResultsOne homozygous non-sense mutation (NM_194302, c.G5341T:p.E1781X), two compound heterozygous mutations (c.C2284T:p.R762X and c.1751delC:p.P584fs) and two compound heterozygous mutations (c.5714_5721del:p.L1905fs and c.C3021A:p.N1007K) were identified in CFAP65 of three individuals with completely immotile spermatozoa, respectively. No biallelic deleterious variants of CFAP65 were detected in the control cohort of 637 individuals. Ultrastructural and immunostaining analyses of spermatozoa from two patients showed highly aberrant sperm morphology with severe defects such as acrosome hypoplasia, disruption of the mitochondrial sheath and absence of the central pair complex.ConclusionTo the best of our knowledge, we are the first to report that CFAP65 mutations may cause spermatozoa to be completely immotile.

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Identification and targeted management of a neurodegenerative disorder caused by biallelic mutations in SLC5A6

npj Genomic Medicine ◽

10.1038/s41525-019-0103-x ◽

2019 ◽

Vol 4 (1) ◽

Cited By ~ 1

Author(s):

Alicia B. Byrne ◽

Peer Arts ◽

Steven W. Polyak ◽

Jinghua Feng ◽

Andreas W. Schreiber ◽

...

Keyword(s):

Neurodegenerative Disorder ◽

Genetic Disorder ◽

Epileptic Encephalopathy ◽

Compound Heterozygous ◽

Whole Exome ◽

Sodium Dependent ◽

Neuromotor Function ◽

Vitamin Uptake ◽

Compound Heterozygous Variants ◽

Biallelic Mutations

AbstractWe describe a sibling pair displaying an early infantile-onset, progressive neurodegenerative phenotype, with symptoms of developmental delay and epileptic encephalopathy developing from 12 to 14 months of age. Using whole exome sequencing, compound heterozygous variants were identified in SLC5A6, which encodes the sodium-dependent multivitamin transporter (SMVT) protein. SMVT is an important transporter of the B-group vitamins biotin, pantothenate, and lipoate. The protein is ubiquitously expressed and has major roles in vitamin uptake in the digestive system, as well as transport of these vitamins across the blood–brain barrier. Pathogenicity of the identified variants was demonstrated by impaired biotin uptake of mutant SMVT. Identification of this vitamin transporter as the genetic basis of this disorder guided targeted therapeutic intervention, resulting clinically in improvement of the patient’s neurocognitive and neuromotor function. This is the second report of biallelic mutations in SLC5A6 leading to a neurodegenerative disorder due to impaired biotin, pantothenate and lipoate uptake. The genetic and phenotypic overlap of these cases confirms mutations in SLC5A6 as the genetic cause of this disease phenotype. Recognition of the genetic disorder caused by SLC5A6 mutations is essential for early diagnosis and to facilitate timely intervention by triple vitamin (biotin, pantothenate, and lipoate) replacement therapy.

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Biallelic novel mutations of the COL27A1 gene in a patient with Steel syndrome

Human Genome Variation ◽

10.1038/s41439-021-00149-7 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Jong Seop Kim ◽

Hyoungseok Jeon ◽

Hyeran Lee ◽

Jung Min Ko ◽

Yonghwan Kim ◽

...

Keyword(s):

Hip Dysplasia ◽

Large Deletion ◽

Compound Heterozygous ◽

Radial Head Dislocation ◽

Sequencing Data ◽

Novel Mutations ◽

Exome Sequencing Data ◽

Whole Exome ◽

Whole Exome Sequencing Data ◽

Carpal Coalition

AbstractAn 11-year-old Korean boy presented with short stature, hip dysplasia, radial head dislocation, carpal coalition, genu valgum, and fixed patellar dislocation and was clinically diagnosed with Steel syndrome. Scrutinizing the trio whole-exome sequencing data revealed novel compound heterozygous mutations of COL27A1 (c.[4229_4233dup]; [3718_5436del], p.[Gly1412Argfs*157];[Gly1240_Lys1812del]) in the proband, which were inherited from heterozygous parents. The maternal mutation was a large deletion encompassing exons 38–60, which was challenging to detect.

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Novel variants in DNAH9 lead to nonsyndromic severe asthenozoospermia

Reproductive Biology and Endocrinology ◽

10.1186/s12958-021-00709-0 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Dongdong Tang ◽

Yanwei Sha ◽

Yang Gao ◽

Jingjing Zhang ◽

Huiru Cheng ◽

...

Keyword(s):

Sanger Sequencing ◽

Sperm Morphology ◽

Immunofluorescence Staining ◽

Compound Heterozygous ◽

Sperm Tail ◽

Transmission Electron ◽

Whole Exome ◽

Detailed Medical History ◽

Novel Variants ◽

Common Causes

Abstract Background Asthenozoospermia is one of the most common causes of male infertility, and its genetic etiology is poorly understood. DNAH9 is a core component of outer dynein arms in cilia and flagellum. It was reported that variants of DNAH9 (OMIM: 603330) might cause primary ciliary dyskinesia (PCD). However, variants in DNAH9 lead to nonsyndromic severe asthenozoospermia have yet to be reported. Methods Whole exome sequencing (WES) was performed for two individuals with nonsyndromic severe asthenozoospermia from two non-consanguineous families, and Sanger sequencing was performed to verify the identified variants and parental origins. Sperm routine analysis, sperm vitality rate and sperm morphology analysis were performed according the WHO guidelines 2010 (5th edition). Transmission electron microscopy (TEM, TECNAI-10, 80 kV, Philips, Holland) was used to observe ultrastructures of sperm tail. Quantitative realtime-PCR and immunofluorescence staining were performed to detect the expression of DNAH9-mRNA and location of DNAH9-protein. Furthermore, assisted reproductive procedures were applied. Results By WES and Sanger sequencing, compound heterozygous DNAH9 (NM_001372.4) variants were identified in the two individuals with nonsyndromic severe asthenozoospermia (F1 II-1: c.302dupT, p.Leu101fs*47 / c.6956A > G, p.Asp2319Gly; F2 II-1: c.6294 T > A, p.Phe2098Leu / c.10571 T > A, p.Leu3524Gln). Progressive rates less than 1% with normal sperm morphology rates and normal vitality rates were found in both of the two subjects. No respiratory phenotypes, situs inversus or other malformations were found by detailed medical history, physical examination and lung CT scans etc. Moreover, the expression of DNAH9-mRNA was significantly decreased in sperm from F1 II-1. And expression of DNAH9 is lower in sperm tail by immunofluorescence staining in F1 II-1 compared with normal control. Notably, by intracytoplasmic sperm injection (ICSI), F1 II-1 and his partner successfully achieved clinical pregnancy. Conclusions We identified DNAH9 as a novel pathogenic gene for nonsyndromic severe asthenospermia, and ICSI can contribute to favorable pregnancy outcomes for these patients.

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Rare Variants in Autophagy and Non-Autophagy Genes in Late-Onset Pompe Disease: Suggestions of Their Disease-Modifying Role in Two Italian Families

International Journal of Molecular Sciences ◽

10.3390/ijms22073625 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3625

Author(s):

Filomena Napolitano ◽

Giorgia Bruno ◽

Chiara Terracciano ◽

Giuseppina Franzese ◽

Nicole Piera Palomba ◽

...

Keyword(s):

Pompe Disease ◽

Rare Variants ◽

Clinical Symptoms ◽

Late Onset ◽

Respiratory Muscles ◽

Autosomal Recessive Disorder ◽

Compound Heterozygous ◽

Enzyme Replacement ◽

Whole Exome ◽

Clinical Pictures

Pompe disease is an autosomal recessive disorder caused by a deficiency in the enzyme acid alpha-glucosidase. The late-onset form of Pompe disease (LOPD) is characterized by a slowly progressing proximal muscle weakness, often involving respiratory muscles. In LOPD, the levels of GAA enzyme activity and the severity of the clinical pictures may be highly variable among individuals, even in those who harbour the same combination of GAA mutations. The result is an unpredictable genotype–phenotype correlation. The purpose of this study was to identify the genetic factors responsible for the progression, severity and drug response in LOPD. We report here on a detailed clinical, morphological and genetic study, including a whole exome sequencing (WES) analysis of 11 adult LOPD siblings belonging to two Italian families carrying compound heterozygous GAA mutations. We disclosed a heterogeneous pattern of myopathic impairment, associated, among others, with cardiac defects, intracranial vessels abnormality, osteoporosis, vitamin D deficiency, obesity and adverse response to enzyme replacement therapy (ERT). We identified deleterious variants in the genes involved in autophagy, immunity and bone metabolism, which contributed to the severity of the clinical symptoms observed in the LOPD patients. This study emphasizes the multisystem nature of LOPD and highlights the polygenic nature of the complex phenotype disclosed in these patients.

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Whole-exome sequencing identifies a novel compound heterozygous mutation of ANKS6 gene in a Chinese nephronophthisis patient

Clinica Chimica Acta ◽

10.1016/j.cca.2019.10.030 ◽

2020 ◽

Vol 501 ◽

pp. 131-135

Author(s):

Boliang Fang ◽

Jun Guo ◽

Chanjuan Hao ◽

Ruolan Guo ◽

Suyun Qian ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Whole Exome

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Biallelic Mutations in Ubiquitin-Specific Peptidase 53 (USP53) Causing Progressive Intrahepatic Cholestasis. Report of a Case With Review of Literature

Pediatric and Developmental Pathology ◽

10.1177/10935266211051175 ◽

2021 ◽

pp. 109352662110511

Author(s):

Mukul Vij ◽

Srinivas Sankaranarayanan

Keyword(s):

Liver Transplantation ◽

Liver Disease ◽

Liver Biopsy ◽

Intrahepatic Cholestasis ◽

Cholestatic Liver Disease ◽

Review Of Literature ◽

Biallelic Mutation ◽

Whole Exome ◽

Sequencing Studies ◽

Biallelic Mutations

Whole-exome sequencing studies have recently identified novel genes implicated in normal- or low-GGT pediatric cholestasis including ubiquitin-specific peptidase 53 ( USP53). We identified novel biallelic mutations in the USP53 gene in a 7-month-old infant with pruritus and progressive intrahepatic cholestasis. His liver biopsy showed portal and perivenular fibrosis with bland bilirubinostasis. His parents were asymptomatic heterozygous for the same mutation. He is currently on vitamin supplements and cholestyramine and his family has also been counseled for liver transplantation. Our report confirms that patients with biallelic mutation in USP53 develop cholestatic liver disease.

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Biallelic mutations in EXOC3L2 cause a novel syndrome that affects the brain, kidney and blood

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105421 ◽

2018 ◽

Vol 56 (5) ◽

pp. 340-346

Author(s):

Adel Shalata ◽

Supanun Lauhasurayotin ◽

Zvi Leibovitz ◽

Hongbing Li ◽

Diane Hebert ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Failure ◽

Renal Dysplasia ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Dandy Walker Malformation ◽

Whole Exome ◽

Pituitary Hypoplasia ◽

Walker Malformation ◽

Biallelic Mutations

BackgroundDandy-Walker malformation features agenesis/hypoplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle and enlargement of posterior fossa. Although Dandy-Walker malformation is relatively common and several genes were linked to the syndrome, the genetic cause in the majority of cases is unknown.ObjectiveTo identify the mutated gene responsible for Dandy-Walker malformation, kidney disease and bone marrow failure in four patients from two unrelated families.MethodsMedical assessment, sonographic, MRI and pathological studies were used to define phenotype. Chromosomal microarray analysis and whole-exome sequence were performed to unravel the genotype.ResultsWe report four subjects from two unrelated families with homozygous mutations in the Exocyst Complex Component 3-Like-2 gene (EXOC3L2).EXOC3L2 functions in trafficking of post-Golgi vesicles to the plasma membrane. In the first family a missense mutation in a highly conserved amino acid, p.Leu41Gln, was found in three fetuses; all had severe forms of Dandy-Walker malformation that was detectable by prenatal ultrasonography and confirmed by autopsy. In the second family, the affected child carried a nonsense mutation, p.Arg72*, and no detected protein. He had peritrigonal and cerebellar white matter abnormalities with enlargement of the ventricular trigones, developmental delay, pituitary hypoplasia, severe renal dysplasia and bone marrow failure.ConclusionWe propose that biallelic EXOC3L2 mutations lead to a novel syndrome that affects hindbrain development, kidney and possibly the bone marrow.

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