Phenotypic Variability of MEGF10 Variants Causing Congenital Myopathy: Report of Two Unrelated Patients from a Highly Consanguineous Population

Congenital myopathies are rare neuromuscular hereditary disorders that manifest at birth or during infancy and usually appear with muscle weakness and hypotonia. One of such disorders, early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD, OMIM: 614399, MIM: 612453), is a rare autosomal recessive disorder caused by biallelic mutations (at homozygous or compound heterozygous status) in MEGF10 (multiple epidermal growth factor-like domains protein family). Here, we report two unrelated patients, who were born to consanguineous parents, having two novel MEGF10 deleterious variants. Interestingly, the presence of MEGF10 associated EMARDD has not been reported in Saudi Arabia, a highly consanguineous population. Moreover, both variants lead to a different phenotypic onset of mild and severe types. Our work expands phenotypic features of the disease and provides an opportunity for genetic counseling to the inflicted families.

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Case report: two novel VPS13B mutations in a Chinese family with Cohen syndrome and hyperlinear palms

BMC Medical Genetics ◽

10.1186/s12881-019-0920-x ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 3

Author(s):

Sha Zhao ◽

Zhenqing Luo ◽

Zhenghui Xiao ◽

Liping Li ◽

Rui Zhao ◽

...

Keyword(s):

Developmental Delay ◽

Chinese Population ◽

Autosomal Recessive ◽

Autosomal Recessive Disorder ◽

Chinese Family ◽

Compound Heterozygous ◽

Case Presentation ◽

Cohen Syndrome ◽

The Family ◽

Sporadic Cases

Abstract Background Cohen syndrome (CS) is an uncommon developmental disease with evident clinical heterogeneity. VPS13B is the only gene responsible for CS. Only few sporadic cases of CS have been reported in China. Case presentation A Chinese family with two offspring–patients affected by developmental delay and intellectual disability was investigated in this study. Exome sequencing was performed, and compound heterozygous mutations in VPS13B were segregated for family members with autosomal recessive disorder. Splicing mutation c.3666 + 1G > T (exon 24) and nonsense mutation c. 9844 A > T:p.K3282X (exon 54) were novel. We revisited the family and learned that both patients are affected by microcephaly, developmental delay, neutropenia, and myopia and have a friendly disposition, all of which are consistent with CS phenotypes. We also found that both patients have hyperlinear palms, which their parents do not have. VPS13B mutations reported among the Chinese population were reviewed accordingly. Conclusions This study presents two novel VPS13B mutations in CS. The identification of hyperlinear palms in a family affected by CS expands the phenotype spectrum of CS.

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Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency: late diagnosis and gender reassignment in a two-year-old child

Problems of Endocrinology ◽

10.14341/probl12749 ◽

2021 ◽

Vol 67 (5) ◽

pp. 53-57

Author(s):

N. Yu. Raygorodskaya ◽

E. P. Novikova ◽

A. N. Tyulpakov ◽

M. A. Kareva ◽

N. A. Nikolaeva ◽

...

Keyword(s):

Autosomal Recessive ◽

Clinical Case ◽

Clinical Manifestations ◽

Autosomal Recessive Disorder ◽

Compound Heterozygous ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Gender Reassignment ◽

And Gender ◽

21 Hydroxylase Deficiency

11β-hydroxylase deficiency is a rare autosomal recessive disorder due to impaired steroidogenesis in the adrenal cortex caused by pathogenic mutations in the CYP11B1 gene. The main clinical manifestations are determined by a deficiency of cortisol, ACTH hyperproduction, excessive androgens secretion and the accumulation of 11-deoxycorticosterone, which leads to the development of arterial hypertension. In the diagnostic search, it is important to take into account the ethnicity of the patient, since the frequency of the disease and the prevalence of mutations differ between ethnic groups. The article presents a clinical case of 11β-hydroxylase deficiency as the result of compound heterozygous mutations in the CYP11B1 gene in a patient of Turkic origin. This case shows the clinical manifestations and the development of complications of 11β-hydroxylase deficiency, the stages of differential diagnosis of patients with 21-hydroxylase deficiency.

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Compound heterozygous variants in the ABCG8 gene in a Japanese girl with sitosterolemia

Human Genome Variation ◽

10.1038/s41439-020-00112-y ◽

2020 ◽

Vol 7 (1) ◽

Author(s):

Nobuhiro Hashimoto ◽

Sumito Dateki ◽

Eri Suzuki ◽

Takatoshi Tsuchihashi ◽

Aiko Isobe ◽

...

Keyword(s):

Plant Sterol ◽

Autosomal Recessive ◽

Elevated Serum ◽

Asian Population ◽

Autosomal Recessive Disorder ◽

Compound Heterozygous ◽

Heterozygous State ◽

Single Nucleotide ◽

Compound Heterozygous Variants ◽

Compound Heterozygous State

AbstractSitosterolemia is an autosomal recessive disorder that affects lipid metabolism and is characterized by elevated serum plant sterol levels, xanthomas, and accelerated atherosclerosis. In this study, we report a novel nonsense single-nucleotide variant, c.225G > A (p.Trp75*), and an East Asian population-specific missense multiple-nucleotide variant, c.1256_1257delTCinsAA (p.Ile419Lys), in the ABCG8 gene in a compound heterozygous state observed in a Japanese girl with sitosterolemia.

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3-M syndrome – a primordial short stature disorder with novel CUL7 mutation in two Indian patients

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2021-0412 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Radha Rama Devi Akella

Keyword(s):

Short Stature ◽

Autosomal Recessive ◽

Genetic Diagnosis ◽

Autosomal Recessive Disorder ◽

Missense Variant ◽

Postnatal Growth ◽

Compound Heterozygous ◽

Case Presentation ◽

Whole Exome ◽

Heterozygous Variant

Abstract Objective To evaluate the cause of short stature in children. Case presentation Two children with suspected skeletal dysplasia and short stature were evaluated. Conclusions The 3-M syndrome is a primordial growth disorder manifesting severe postnatal growth restriction, skeletal anomalies and prominent fleshy heels. The 3-M syndrome is a genetically heterogeneous disorder and the phenotype is similar. This is a rare autosomal recessive disorder with normal intellect. Two affected children have been identified by whole-exome sequencing. One patient harboured a compound heterozygous variant and the other was a homozygous missense variant. The genetic diagnosis helped in counselling the families and facilitated prenatal diagnosis in one (case 1) family.

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The genetic basis of classical galactosaemia in Polish patients

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01869-3 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Aleksandra Jezela-Stanek ◽

Anna Bauer ◽

Katarzyna Wertheim-Tysarowska ◽

Jerzy Bal ◽

Agnieszka Magdalena Rygiel ◽

...

Keyword(s):

Autosomal Recessive ◽

Genetic Basis ◽

Dna Analysis ◽

Current Knowledge ◽

Autosomal Recessive Disorder ◽

Molecular Characteristics ◽

Compound Heterozygous ◽

Classic Galactosemia ◽

Pathogenic Variants ◽

Molecular Etiology

AbstractClassic galactosemia (OMIM #230400) is an autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in the galactose-1-phosphate uridylyltransferase gene (GALT; 606999) on chromosome 9p13. Its diagnosis is established by detecting elevated erythrocyte galactose-1-phosphate concentration, reduced erythrocyte galactose-1-phosphate uridylyltransferase (GALT) enzyme activity. Biallelic pathogenic variants in the GALT gene is confirmed by DNA analysis. Our paper presents molecular characteristics of 195 Polish patients diagnosed with galactosemia I, intending to expand the current knowledge of this rare disease's molecular etiology. To the best of our knowledge, the described cohort of galactosemia patients is the largest single-center cohort presented so far.

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Two NovelCYP11B1Gene Mutations in Patients from Two Croatian Families with 11β-Hydroxylase Deficiency

International Journal of Endocrinology ◽

10.1155/2014/185974 ◽

2014 ◽

Vol 2014 ◽

pp. 1-6 ◽

Cited By ~ 7

Author(s):

Katja Dumic ◽

Tony Yuen ◽

Zorana Grubic ◽

Vesna Kusec ◽

Ingeborg Barisic ◽

...

Keyword(s):

Genetic Analysis ◽

Molecular Genetics ◽

Molecular Basis ◽

Autosomal Recessive ◽

Autosomal Recessive Disorder ◽

Compound Heterozygous ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Common Cause ◽

Exon 1

Steroid 11β-hydroxylase deficiency (11β-OHD) is the second most common cause of congenital adrenal hyperplasia. Mutations in theCYP11B1gene, which encodes steroid 11β-hydroxylase, are responsible for this autosomal recessive disorder. Here, we describe the molecular genetics of two previously reported male siblings in whom diagnosis of 11β-OHD has been established based on their hormonal profiles displaying high levels of 11-deoxycortisol and hyperandrogenism. Both patients are compound heterozygous for a novel p.E67fs (c.199delG) mutation in exon 1 and a p.R448H (c.1343G>A) mutation in exon 8. We also report the biochemical and molecular genetics data of one new 11β-OHD patient. Sequencing of theCYP11B1gene reveals that this patient is compound heterozygous for a novel, previously undescribed p.R141Q (c.422G>A) mutation in exon 3 and a p.T318R (c.953C>G) mutation in exon 5. All three patients are of Croatian (Slavic) origin and there is no self-reported consanguinity in these two families. Results of our investigation confirm that most of theCYP11B1mutations are private. In order to elucidate the molecular basis for 11β-OHD in the Croatian/Slavic population, it is imperative to performCYP11B1genetic analysis in more patients from this region, since so far only four patients from three unrelated Croatian families have been analyzed.

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Novel STAC3 Mutations in the First Non-Amerindian Patient with Native American Myopathy

Neuropediatrics ◽

10.1055/s-0037-1601868 ◽

2017 ◽

Vol 48 (06) ◽

pp. 451-455 ◽

Cited By ~ 9

Author(s):

Anne Schänzer ◽

Alexander Pepler ◽

Corina Heller ◽

Bernd Neubauer ◽

Andreas Hahn ◽

...

Keyword(s):

Native American ◽

Malignant Hyperthermia ◽

Autosomal Recessive ◽

Congenital Myopathy ◽

Compound Heterozygous ◽

Homozygous Mutation ◽

Aberrant Splicing ◽

Gene Encoding ◽

Contraction Coupling ◽

Ventilatory Failure

AbstractNative American myopathy (NAM) is an autosomal recessive congenital myopathy, up till now exclusively described in Lumbee Indians who harbor one single homozygous mutation (c.1046G>C, pW284S) in the STAC3 gene, encoding a protein important for proper excitation–contraction coupling in muscle. Here, we report the first non-Amerindian patient of Turkish ancestry, being compound heterozygous for the mutations c.862A>T (p.K288*) and c.432+4A>T (aberrant splicing with skipping of exon 4). Symptoms in NAM include congenital muscle weakness and contractures, progressive scoliosis, early ventilatory failure, a peculiar facial gestalt with mild ptosis and downturned corners of the mouth, short stature, and marked susceptibility to malignant hyperthermia. This case shows that NAM should also be considered in non-Indian patients with congenital myopathy, and suggests that STAC3 mutations should be taken into account as a potential cause of malignant hyperthermia.

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Two Decades after Mandibuloacral Dysplasia Discovery: Additional Cases and Comprehensive View of Disease Characteristics

Genes ◽

10.3390/genes12101508 ◽

2021 ◽

Vol 12 (10) ◽

pp. 1508

Author(s):

Isabelle Jéru ◽

Amira Nabil ◽

Gehad El-Makkawy ◽

Olivier Lascols ◽

Corinne Vigouroux ◽

...

Keyword(s):

Phenotypic Variability ◽

Genetic Disorders ◽

Autosomal Recessive Disorder ◽

Missense Variant ◽

Compound Heterozygous ◽

Partial Lipodystrophy ◽

Mandibular Hypoplasia ◽

Pathogenic Variants ◽

Compound Heterozygous Variants ◽

Mandibuloacral Dysplasia

Pathogenic variants in the LMNA gene cause a group of heterogeneous genetic disorders, called laminopathies. In particular, homozygous or compound heterozygous variants in LMNA have been associated with “mandibuloacral dysplasia type A” (MADA), an autosomal recessive disorder, characterized by mandibular hypoplasia, growth retardation mainly postnatal, pigmentary skin changes, progressive osteolysis of the distal phalanges and/or clavicles, and partial lipodystrophy. The detailed characteristics of this multisystemic disease have yet to be specified due to its rarity and the limited number of cases described. Here, we report three unrelated Egyptian patients with variable severity of MAD features. Next-generation sequencing using a gene panel revealed a homozygous c.1580G>A-p.Arg527His missense variant in LMNA exon 9 in an affected individual with a typical MADA phenotype. Another homozygous c.1580G>T-p.Arg527Leu variant affecting the same amino acid was identified in two additional patients, who both presented with severe manifestations very early in life. We combined our observations together with data from all MADA cases reported in the literature to get a clearer picture of the phenotypic variability in this disease. This work raises the number of reported MADA families, argues for the presence of the founder effect in Egypt, and strengthens genotype–phenotype correlations.

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Novel CUL7 biallelic mutations alter the skeletal phenotype of 3M syndrome

Human Genome Variation ◽

10.1038/s41439-020-0090-6 ◽

2020 ◽

Vol 7 (1) ◽

Author(s):

Nao Takizaki ◽

Yoshinori Tsurusaki ◽

Kaoru Katsumata ◽

Yumi Enomoto ◽

Hiroaki Murakami ◽

...

Keyword(s):

Autosomal Recessive ◽

Neonatal Period ◽

Autosomal Recessive Disorder ◽

Facial Features ◽

Skeletal Changes ◽

Novel Variants ◽

Skeletal Phenotype ◽

Vertebral Bodies ◽

Biallelic Mutations ◽

Severe Growth

Abstract3M syndrome is an autosomal recessive disorder characterized by severe growth retardation, distinct facial features, and skeletal changes, including long slender tubular bones and tall vertebral bodies. We report a Japanese patient with 3M syndrome caused by the biallelic novel variants c.1705_1708del and c.1989_1999del of CUL7. Skeletal features were consistent with 3M syndrome in the early neonatal period but became less obvious by 2 years of age.

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A case of pyridoxine-dependent epilepsy with novel ALDH7A1 mutations

Oxford Medical Case Reports ◽

10.1093/omcr/omaa008 ◽

2020 ◽

Vol 2020 (3) ◽

Author(s):

Yuri Dowa ◽

Takashi Shiihara ◽

Tomoyuki Akiyama ◽

Kosei Hasegawa ◽

Fumitaka Inoue ◽

...

Keyword(s):

Vitamin B6 ◽

Autosomal Recessive ◽

Pyridoxal Phosphate ◽

Birth Asphyxia ◽

Autosomal Recessive Disorder ◽

Pulmonary Haemorrhage ◽

Neonatal Seizure ◽

Cerebral White Matter ◽

Compound Heterozygous ◽

Semialdehyde Dehydrogenase

Abstract Pyridoxine-dependent epilepsy (PDE) is a rare autosomal-recessive disorder typically presenting with neonatal seizures and is sometimes difficult to diagnose, because the clinical features mimic those of birth asphyxia. A Japanese newborn boy presented with pulmonary haemorrhage and convulsions on the day of birth. Brain computed tomography showed diffuse, but mild, low-density cerebral white matter and a thin subdural hematoma in the posterior fossa. He did not have thrombocytopenia or coagulopathy. His respiratory status improved with conservative treatment, but his convulsions were persistent even after prescription of several antiepileptic drugs. His serum and cerebrospinal fluid showed decreased vitamin B6 vitamers and increased upstream metabolites of α-aminoadipic semialdehyde dehydrogenase, strongly suggesting a diagnosis of PDE; the epileptic spasms ceased after administration of intravenous pyridoxal phosphate hydrate. Gene analysis revealed novel compound heterozygous mutations in ALDH7A1 that included NM_001182.4:[c.1196G > T] and [c.1200 + 1G > A]. Atypical birth asphyxia with persistent neonatal seizure should prompt vitamin B6/metabolite screening.

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