Combination of Novel c.3484G> T/p.Glu162Ter Variant in ABCB11 and c.208G> A/p.Asp70Asn Variant in ATP8B1 Are Associated with Severe Symptoms in Progressive Family Intrahepatic Cholestasis

AbstractProgressive family intrahepatic cholestasis (PFIC) is an autosomal recessive disease that causes chronic cholestasis. It is associated with pathogenic variants in genes that encode proteins involved in bile secretion to canaliculus from hepatocytes. In this study, we present a 16-year-old boy who presented with severe pruritus and cholestatic jaundice. All possible infectious etiologies were negative. A liver biopsy was consistent with intrahepatic cholestasis and portal fibrosis. DNA was isolated from a peripheral blood sample, and whole exome sequencing was performed. A novel c.3484G > T/p.Glu162Ter variant in the ABCB11 gene and a c.208G> A/p.Asp70Asn variant in the ATP8B1 gene were detected. Despite traditional treatment, the patient's recurrent severe symptoms did not improve. The patient was referred for a liver transplantation. This novel c.3484G > T/p.Glu162Ter variant is associated with a severe and recurrent presentation, and the two compound variants could explain the severity of PFIC.

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Novel COL11A2 Pathogenic Variants in a Child with Autosomal Recessive Otospondylomegaepiphyseal Dysplasia: A Review of the Literature

Journal of Pediatric Genetics ◽

10.1055/s-0039-1698446 ◽

2019 ◽

Vol 09 (02) ◽

pp. 117-120

Author(s):

Pavalan Selvam ◽

Shekhar Singh ◽

Angita Jain ◽

Herjot Atwal ◽

Paldeep S. Atwal

Keyword(s):

Sequence Analysis ◽

Autosomal Recessive ◽

Autosomal Dominant ◽

Review Of The Literature ◽

Pathogenic Variants ◽

Phenotypic Spectrum ◽

Whole Exome ◽

The Family ◽

Type Xi Collagen ◽

Exome Sequence

AbstractOtospondylomegaepiphyseal dysplasia (OSMED) is an inherited autosomal dominant and recessive skeletal dysplasia caused by both heterozygous and homozygous pathogenic variants in COL11A2 encoding the α2(XI) collagen chains, a part of type XI collagen. Here, we describe a 2-year-old girl presenting from birth with a phenotype suggestive of OSMED. On whole exome sequence analysis of the family via commercially available methods, we detected two novel heterozygous pathogenic variants in the proband. In addition, we reviewed the phenotype of autosomal recessive OSMED cases with COL11A2 pathogenic variants reported to date and quantitatively highlighted the phenotypic spectrum.

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A novel autosomal recessive lipodystrophy syndrome due to homozygous LMNA variant

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106395 ◽

2019 ◽

Vol 57 (6) ◽

pp. 422-426 ◽

Cited By ~ 1

Author(s):

Nivedita Patni ◽

Sarah Hatab ◽

Chao Xing ◽

Zhengyang Zhou ◽

Claudia Quittner ◽

...

Keyword(s):

Autosomal Recessive ◽

Acanthosis Nigricans ◽

Subcutaneous Fat ◽

Subsequent Development ◽

Muscular Hypertrophy ◽

Lipodystrophy Syndrome ◽

Pathogenic Variants ◽

Whole Exome ◽

Upper And Lower Extremities ◽

Mandibuloacral Dysplasia

BackgroundDespite major advances in understanding the molecular basis of various genetic lipodystrophy syndromes, some rare patients still remain unexplained.CasesWe report a novel autosomal recessive lipodystrophy affecting two sisters aged 17 and 19 years and characterised by early onset intellectual disability, and subsequent development of near-generalised loss of subcutaneous fat with diabetes mellitus, extreme hypertriglyceridemia, hepatic steatosis, short stature, clinodactyly, joint contractures, leiomyoma of uterus and cataracts in childhood. The lipodystrophy was more pronounced in the upper and lower extremities, and there was no associated muscular hypertrophy. Using whole exome sequencing in this consanguineous Hispanic pedigree, we report disease-causing homozygous p.Arg545His LMNA variant in the affected subjects, and confirm the lack of pathogenic variants in other known lipodystrophy genes. The mother and a younger brother were both heterozygous for p.Arg545His LMNA variant and were overweight with acanthosis nigricans without any evidence of lipodystrophy. Our patients are distinct from previously reported autosomal recessive lipodystrophy syndromes and have no overlap with other autosomal recessive laminopathies, including mandibuloacral dysplasia, Emery-Dreifuss muscular dystrophy and Charcot-Marie-Tooth neuropathy.ConclusionOur report of this unusual familial generalised lipodystrophy syndrome adds to the pleiotropy associated with biallelic autosomal recessive LMNA variants.

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Identification of two novel pathogenic variants of PIBF1 by whole exome sequencing in a 2-year-old boy with Joubert syndrome

BMC Medical Genetics ◽

10.1186/s12881-020-01130-x ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Yue Shen ◽

Hao Wang ◽

Zhimin Liu ◽

Minna Luo ◽

Siyu Ma ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Autosomal Recessive ◽

Autosomal Recessive Disorder ◽

Autosomal Recessive Inheritance ◽

Joubert Syndrome ◽

Causative Gene ◽

Pathogenic Variants ◽

Whole Exome ◽

Syndrome Individual

Abstract Background Joubert syndrome (OMIM 213300) is an autosomal recessive disorder with gene heterogeneity. Causal genes and their variants have been identified by sequencing or other technologies for Joubert syndrome subtypes. Case presentation A two-year-old boy was diagnosed with Joubert syndrome by global development delay and molar tooth sign of mid-brain. Whole exome sequencing was performed to detect the causative gene variants in this individual, and the candidate pathogenic variants were verified by Sanger sequencing. We identified two pathogenic variants (NM_006346.2: c.1147delC and c.1054A > G) of PIBF1 in this Joubert syndrome individual, which is consistent with the mode of autosomal recessive inheritance. Conclusion In this study, we identified two novel pathogenic variants in PIBF1 in a Joubert syndrome individual using whole exome sequencing, thereby expanding the PIBF1 pathogenic variant spectrum of Joubert syndrome.

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Novel variants identified in CKAP2L in two siblings with Filippi Syndrome

Molecular Case Studies ◽

10.1101/mcs.a006130 ◽

2021 ◽

pp. mcs.a006130

Author(s):

Ryan J Patrick ◽

Jill M Weimer ◽

Laura Davis-Keppen ◽

Megan L Landsverk

Keyword(s):

Intellectual Disability ◽

Autosomal Recessive ◽

Missense Variant ◽

Facial Features ◽

Loss Of Function ◽

Pathogenic Variants ◽

Whole Exome ◽

The Family ◽

Novel Variants ◽

In Trans

Pathogenic variants in CKAP2L have previously been reported in Filippi Syndrome (FS), a rare autosomal recessive, craniodigital syndrome characterized by microcephaly, syndactyly, short stature, intellectual disability, and dysmorphic facial features. To date, fewer than ten patients with pathogenic variants in CKAP2L associated with FS have been reported. All of the previously reported probands have presumed loss-of-function variants (frameshift, canonical splice site, starting methionine) and all but one have been homozygous for a pathogenic variant. Here we describe two brothers who presented with microcephaly, micrognathia, syndactyly, dysmorphic features, and intellectual disability. Whole exome sequencing of the family identified a missense variant, c.2066G>A (p.Arg689His), in trans with a frameshift variant, c.1169_1173del (p.Ile390LysfsTer4), in CKAP2L. To our knowledge, these are the first patients with FS to be reported with a missense variant in CKAP2L and only the second family to be reported with two variants in trans.

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Three Novel Variants of CEP290 and CC2D2DA and a Link Between ZNF77 and SHH Signaling Pathway Are Found in Two Meckel-Gruber Syndrome Fetuses

Reproductive Sciences ◽

10.1007/s43032-021-00835-5 ◽

2022 ◽

Author(s):

Zhidan Hong ◽

Xuanyi He ◽

Fang Yu ◽

Huanyu Liu ◽

Xiaoli Zhang ◽

...

Keyword(s):

Autosomal Recessive ◽

Pathological Examination ◽

Compound Heterozygous ◽

Over Expression ◽

Pathogenic Variants ◽

Whole Exome ◽

The Family ◽

Novel Variants ◽

Novel Variant ◽

Missed Diagnosis

AbstractMeckel-Gruber syndrome (MKS) is a rare lethal autosomal recessive inherited disorder. Missed diagnosis might happen in clinical works due to an unclear genotype–phenotype correlation. We analyzed two families visiting our center; the parents are normal; each of the family aborted a fetus at 12WG. Following ultrasonography and pathological examination, both were diagnosed as MKS. Whole exome sequencing identified a compound heterozygous of two novel variants of CEP290 and a heterozygous of a novel variant of CC2D2A. Frameshift mutations in ZNF77 were also detected. Western blot analyzing whole-brain tissue showed that the expression of ZNF77, CC2D2A, and CEP290 was enhanced. HEK293T transfected with over-expression wildtype/mutated ZNF77 plasmid showed that SHH was increased in wildtype ZNF77 cells, while SHH and CC2D2A were increased in mutated ZNF77 cells. Our research provided two novel pathogenic variants of CEP290 and CC2D2A and suggested that ZNF77 might promote the expression of CC2D2A and regulate the amount of SHH.

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Novel mutation in the RAB3GAP1 gene, the first diagnosed Warburg Micro syndrome case in Syria

Oxford Medical Case Reports ◽

10.1093/omcr/omaa031 ◽

2020 ◽

Vol 2020 (4-5) ◽

Author(s):

Soubhi Tenawi ◽

Rawan Al Khudari ◽

Diana Alasmar

Keyword(s):

Autosomal Recessive ◽

Autosomal Recessive Disease ◽

Novel Mutation ◽

Homozygous Mutation ◽

Muscular Hypotonia ◽

Congenital Cataracts ◽

Whole Exome ◽

Warburg Micro Syndrome ◽

Rare Autosomal Recessive Disease

Abstract Warburg Micro syndrome is a rare autosomal recessive disease due to mutation in the RAB3GAP1, RAB3GAP2, RAB18 and TBC1D20 genes. It is commonly seen in consanguineous marriages, characterized by optic (microcornea, microphthalmia, congenital cataracts), neurologic )microcephaly, corpus callosum hypoplasia, severe mental retardation( and hypogonadism; some non-typical findings could be present (cardiomyopathy, peripheral neuropathy). We report a novel homozygous mutation in the RAB3GAP1 gene in a 7-month-old boy from healthy nonconsanguineous parents from the same village in Syria, with bilateral congenital cataracts, hypogonadism, muscular hypotonia and severe developmental delay. Whole exome sequencing (WES) showed a homozygous mutation in the c.2195del p.(Pro732Glnfs*6) in exon 19 of the RAB3GAP1 gene, which is likely pathogenic and correlates with Warburg Micro syndrome type 1.

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The spectrum of CFTR gene pathogenic variants in Northern Ossetia

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2020.07.57-59 ◽

2020 ◽

pp. 57-59

Author(s):

Н.В. Балинова ◽

Н.В. Петрова ◽

З.К. Гетоева ◽

Н.Ю. Каширская ◽

Т.А. Васильева ◽

...

Keyword(s):

Cystic Fibrosis ◽

Chloride Channel ◽

Autosomal Recessive ◽

Autosomal Recessive Disease ◽

Cftr Gene ◽

Gene Variants ◽

Healthy Individuals ◽

Pathogenic Variants ◽

The Republic ◽

North Ossetia

Муковисцидоз (МВ) - аутосомно-рецессивное заболевание, обусловленное нарушением функции эпителиального хлорного канала, кодируемого геном CFTR. Спектр и частота вариантов последовательности гена CFTR, как и частота МВ различаются в разных странах и этнических группах. Изучено распределение частот вариантов гена CFTR у больных МВ и у здоровых индивидов в Республике Северной Осетия-Алания. Спектр патогенных вариантов у осетинских больных МВ отличается своеобразием: наиболее частыми являются два варианта W1282X (50%) и F508del (20%), тогда как в общероссийской выборке пациентов самыми частыми являются варианты F508del (52,8%) и CFTRdele2,3 (6,2%), а вариант W1282X (1,90%) относительно редок. В выборке здоровых осетин частоты выявленных вариантов W1282X и F508del составляют 0,0032 и 0,0016, соответственно. Cystic fibrosis (CF) is an autosomal recessive disease caused by impaired function of the epithelial chloride channel encoded by the CFTR gene. The spectrum and frequency of CFTR gene variants, as well as the CF incidence, vary in different countries and ethnic groups. The frequency distribution of CFTR gene variants in CF patients and in healthy individuals in the Republic of North Ossetia-Alania was studied. The spectrum of pathogenic variants in Ossetian CF patients is specific: the most frequent are two variants W1282X (50%) and F508del (20%), while in the all-Russian CF patients the most frequent are variants - F508del (52.8%) and CFTRdele2.3 (6.2%), and the variant W1282X (1.90%) is relatively rare. In healthy Ossetians, the frequencies of detected variants W1282X and F508del are 0.0032 and 0.0016, respectively. The most common CFTR gene variants are W1282X and F508del, found both in CF patients and healthy individuals from the Ossetian population of the Republic of North Ossetia-Alania.

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MCAD deficiency caused by compound heterozygous pathogenic variants in ACADM

Human Genome Variation ◽

10.1038/s41439-021-00177-3 ◽

2022 ◽

Vol 9 (1) ◽

Author(s):

Fumikatsu Nohara ◽

Go Tajima ◽

Hideo Sasai ◽

Yoshio Makita

Keyword(s):

Autosomal Recessive ◽

Autosomal Recessive Disease ◽

Residual Activity ◽

Complete Loss ◽

Compound Heterozygous ◽

Limit Of Quantification ◽

Mcad Deficiency ◽

Pathogenic Variants ◽

Chain Acyl ◽

Acyl Coenzyme A

AbstractMedium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is an autosomal recessive disease caused by biallelic pathogenic ACADM variants. We report a case of an asymptomatic Japanese girl with MCAD deficiency caused by compound heterozygous pathogenic variants (NM_000016.5:c.1040G > T (p.Gly347Val) and c.449_452delCTGA (p.Thr150ArgfsTer4)). Because the MCAD residual activity in lymphocytes of the patient was below the limit of quantification, both variants are likely to cause complete loss of MCAD enzymatic activity.

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Genetics of alkaptonuria – an overview

Acta Facultatis Pharmaceuticae Universitatis Comenianae ◽

10.1515/afpuc-2015-0021 ◽

2015 ◽

Vol 62 (s11) ◽

pp. 27-32

Author(s):

Andrea Zatkova ◽

Martina Nemethova

Keyword(s):

Inborn Error ◽

Autosomal Recessive ◽

Autosomal Recessive Disease ◽

Homogentisic Acid ◽

Compound Heterozygous ◽

Ochronotic Arthropathy ◽

Pathogenic Variants ◽

Gene Coding ◽

Metabolic Block ◽

Rare Autosomal Recessive Disease

Abstract Alkaptonuria (AKU) is the first described inborn error of metabolism and a classical example of rare autosomal recessive disease. AKU patients carry homozygous or compound heterozygous mutations of the gene coding for enzyme homogentisate dioxygenase (HGD) involved in metabolism of tyrosine. The metabolic block in AKU causes accumulation of homogentisic acid (HGA) that, with advancing age of the patient, leads to severe and painful ochronotic arthropathy. HGD gene was mapped to chromosome 3q13.3 and is composed of 14 exons. In about 400 patients, 142 pathogenic variants were reported that are listed in HGD mutations database (http://hgddatabase.cvtisr.sk/). In this review, we summarise different aspects of AKU genetics and impact of the HGD variants on enzyme function.

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Plasma Transfusion Combined with Chelating Therapy Alleviates Fulminant Wilson’s Disease with a Single Arg778Leu Heterozygote Mutation

Annals of Hepatology ◽

10.5604/01.3001.0012.4896 ◽

2018 ◽

Vol 17 (5) ◽

pp. 0-10

Author(s):

Longgen Liu ◽

Qing Gong ◽

Juan Liu ◽

Hongyu Shen ◽

Hongyu Zhang ◽

...

Keyword(s):

Autosomal Recessive ◽

Wilson’S Disease ◽

Autosomal Recessive Disease ◽

Prognostic Index ◽

Wilson's Disease ◽

Plasma Transfusion ◽

Liver Support ◽

Artificial Liver Support ◽

Whole Exome ◽

Chelating Therapy

Wilson’s disease (WD), resulting from homozygote and compound heterozygote mutations in ATB7B, is an autosomal recessive disease. WD associated acute liver failure (ALF) is fatal, and a revised Wilson’s disease prognostic index (RWPI) > 11 is a reliable indication of liver transplantation (LT) or artificial liver support (ALS). We described a WD patient who initially presented with ALF and severe hemolytic anemia. A single heterozygote c.2333G > T mutation (p. Arg778Leu, R778L) in ATP7B was screened by whole exome sequencing and validated by Sanger sequencing. Rapid diagnostic criteria (ALP/TBIL < 4 and AST/ALT > 2.2) are suitable for early diagnosis. Although the RWPI amounted to 15, the patient recovered after intermittent plasma transfusion and subsequent chelating therapy without LT or ALS. In conclusion, WD patients with a single R778L heterozygote mutation can present with ALF as the initial clinical manifestation, and intermittent plasma transfusion combined with chelating therapy may alleviate fulminant WD without LT or ALS.

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