Interpretation of Autosomal Recessive Kidney Diseases With “Presumed Homozygous” Pathogenic Variants Should Consider Technical Pitfalls

Abstract Background Autosomal recessive Alport syndrome (ARAS) is caused by pathogenic variants in both alleles of either COL4A3 or COL4A4 genes. Reports on ARAS are rare due to small patient numbers and there are no reports on renin-angiotensin-aldosterone system (RAAS) inhibition therapy in ARAS. Methods Retrospective study in 101 patients with ARAS from Chinese Registry Database of Hereditary Kidney Diseases and European Alport Registry. Genotype–phenotype correlations and nephroprotective effects of RAAS inhibition in ARAS were evaluated. Results Median age was 15 years (range 1.5–46 years). Twelve patients progressed to stage 5 chronic kidney disease (CKD5) at median age 20.5 years. Patients without missense variants had both higher prevalence and earlier onset age of hearing loss, nephrotic-range proteinuria, more rapid decline of eGFR, and earlier onset age of CKD5 compared to patients with 1 or 2 missense variants. Most patients (79/101, 78%) currently are treated with RAAS inhibitors; median age at therapy initiation was 10 years and mean duration 6.5 ± 6.0 years. Median age at CKD5 for untreated patients was 24 years. RAAS inhibition therapy delayed CKD5 onset in those with impaired kidney function (T-III) to median age 35 years, but is undefined in treated patients with proteinuria (T-II) due to low number of events. No treated patients with microalbuminuria (T-I) progressed to CKD5. ARAS patients with 1 or 2 missense variants showed better response to treatment than patients with non-missense-variants. Conclusions Our study provides the first evidence for early use of RAAS inhibition therapy in patients with ARAS. Furthermore, genotype in ARAS correlates with response to therapy in favor of missense variants.

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Classical Xanthinuria in Nine Israeli Families and Two Isolated Cases from Germany: Molecular, Biochemical and Population Genetics Aspects

Biomedicines ◽

10.3390/biomedicines9070788 ◽

2021 ◽

Vol 9 (7) ◽

pp. 788

Author(s):

Hava Peretz ◽

Ayala Lagziel ◽

Florian Bittner ◽

Mustafa Kabha ◽

Meirav Shtauber-Naamati ◽

...

Keyword(s):

Autosomal Recessive ◽

Heterologous Protein ◽

Heterologous Protein Expression ◽

Type I ◽

Type Ii ◽

Amino Acid Residues ◽

Cysteine Desulfurase ◽

Cofactor Binding ◽

Pathogenic Variants ◽

Expression Studies

Classical xanthinuria is a rare autosomal recessive metabolic disorder caused by variants in the XDH (type I) or MOCOS (type II) genes. Thirteen Israeli kindred (five Jewish and eight Arab) and two isolated cases from Germany were studied between the years 1997 and 2013. Four and a branch of a fifth of these families were previously described. Here, we reported the demographic, clinical, molecular and biochemical characterizations of the remaining cases. Seven out of 20 affected individuals (35%) presented with xanthinuria-related symptoms of varied severity. Among the 10 distinct variants identified, six were novel: c.449G>T (p.(Cys150Phe)), c.1434G>A (p.(Trp478*)), c.1871C>G (p.(Ser624*)) and c.913del (p.(Leu305fs*1)) in the XDH gene and c.1046C>T (p.(Thr349Ileu)) and c.1771C>T (p.(Pro591Ser)) in the MOCOS gene. Heterologous protein expression studies revealed that the p.Cys150Phe variant within the Fe/S-I cluster-binding site impairs XDH biogenesis, the p.Thr349Ileu variant in the NifS-like domain of MOCOS affects protein stability and cysteine desulfurase activity, while the p.Pro591Ser and a previously described p.Arg776Cys variant in the C-terminal domain affect Molybdenum cofactor binding. Based on the results of haplotype analyses and historical genealogy findings, the potential dispersion of the identified variants is discussed. As far as we are aware, this is the largest cohort of xanthinuria cases described so far, substantially expanding the repertoire of pathogenic variants, characterizing structurally and functionally essential amino acid residues in the XDH and MOCOS proteins and addressing the population genetic aspects of classical xanthinuria.

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Diagnostic exome-based preconception carrier testing in consanguineous couples: results from the first 100 couples in clinical practice

Genetics in Medicine ◽

10.1038/s41436-021-01116-x ◽

2021 ◽

Author(s):

Suzanne C. E. H. Sallevelt ◽

Alexander P. A. Stegmann ◽

Bart de Koning ◽

Crool Velter ◽

Anja Steyls ◽

...

Keyword(s):

Autosomal Recessive ◽

Rare Variants ◽

Clinical Care ◽

Carrier Testing ◽

Carrier Status ◽

Routine Diagnostics ◽

Affected Offspring ◽

Pathogenic Variants ◽

Increased Risk ◽

Genetics And Genomics

Abstract Purpose Consanguineous couples are at increased risk of being heterozygous for the same autosomal recessive (AR) disorder(s), with a 25% risk of affected offspring as a consequence. Until recently, comprehensive preconception carrier testing (PCT) for AR disorders was unavailable in routine diagnostics. Here we developed and implemented such a test in routine clinical care. Methods We performed exome sequencing (ES) for 100 consanguineous couples. For each couple, rare variants that could give rise to biallelic variants in offspring were selected. These variants were subsequently filtered against a gene panel consisting of ~2,000 genes associated with known AR disorders (OMIM-based). Remaining variants were classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, after which only likely pathogenic and pathogenic (class IV/V) variants, present in both partners, were reported. Results In 28 of 100 tested consanguineous couples (28%), likely pathogenic and pathogenic variants not previously known in the couple or their family were reported conferring 25% risk of affected offspring. Conclusion ES-based PCT provides a powerful diagnostic tool to identify AR disease carrier status in consanguineous couples. Outcomes provided significant reproductive choices for a higher proportion of these couples than previous tests.

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Spondylocarpotarsal synostosis syndrome due to a novel loss of function FLNB variant: a case report

BMC Musculoskeletal Disorders ◽

10.1186/s12891-020-03890-2 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Samina Yasin ◽

Outi Makitie ◽

Sadaf Naz

Keyword(s):

Short Stature ◽

Autosomal Recessive ◽

Autosomal Recessive Disorder ◽

Loss Of Function ◽

Case Presentation ◽

Pathogenic Variants ◽

Skeletal Malformations ◽

Tarsal Bones ◽

The Family ◽

Heterozygous Carriers

Abstract Background Loss of function or gain of function variants of Filamin B (FLNB) cause recessive or dominant skeletal disorders respectively. Spondylocarpotarsal synostosis syndrome (SCT) is a rare autosomal recessive disorder characterized by short stature, fused vertebrae and fusion of carpal and tarsal bones. We present a novel FLNB homozygous pathogenic variant and present a carrier of the variant with short height. Case presentation We describe a family with five patients affected with skeletal malformations, short stature and vertebral deformities. Exome sequencing revealed a novel homozygous frameshift variant c.2911dupG p.(Ala971GlyfsTer122) in FLNB, segregating with the phenotype in the family. The variant was absent in public databases and 100 ethnically matched control chromosomes. One of the heterozygous carriers of the variant had short stature. Conclusion Our report expands the genetic spectrum of FLNB pathogenic variants. It also indicates a need to assess the heights of other carriers of FLNB recessive variants to explore a possible role in idiopathic short stature.

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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

Journal of Pediatric Genetics ◽

10.1055/s-0039-1700971 ◽

2020 ◽

Vol 09 (04) ◽

pp. 285-288

Author(s):

Mervan Bekdas ◽

Guray Can ◽

Recep Eroz ◽

Selma Erdogan Duzcu

Keyword(s):

Intrahepatic Cholestasis ◽

Autosomal Recessive ◽

Autosomal Recessive Disease ◽

Bile Secretion ◽

Peripheral Blood Sample ◽

Portal Fibrosis ◽

Traditional Treatment ◽

Pathogenic Variants ◽

Chronic Cholestasis ◽

Whole Exome

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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Thiamine Treatment and Favorable Outcome in an Infant with Biallelic TPK1 Variants

Neuropediatrics ◽

10.1055/s-0040-1715631 ◽

2020 ◽

Author(s):

Matthias Eckenweiler ◽

Johannes A. Mayr ◽

Sarah Grünert ◽

Angela Abicht ◽

Rudolf Korinthenberg

Keyword(s):

Early Childhood ◽

Early Diagnosis ◽

Metabolic Disorder ◽

Autosomal Recessive ◽

Psychomotor Development ◽

Compound Heterozygosity ◽

Pathogenic Variants ◽

Clinical Stabilization ◽

Biotin Supplementation ◽

Thiamine Treatment

AbstractEpisodic encephalopathy due to mutations in the thiamine pyrophosphokinase 1 (TPK1) gene is a rare autosomal recessive metabolic disorder. Patients reported so far have onset in early childhood of acute encephalopathic episodes, which result in a progressive neurologic dysfunction including ataxia, dystonia, and spasticity. Here, we report the case of an infant with TPK1 deficiency (compound heterozygosity for two previously described pathogenic variants) presenting with two encephalopathic episodes and clinical stabilization under oral thiamine and biotin supplementation. In contrast to other reported cases, our patient showed an almost normal psychomotor development, which might be due to an early diagnosis and subsequent therapy.

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The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2021.03.004 ◽

2021 ◽

Vol 108 (4) ◽

pp. 608-619

Author(s):

Hila Fridman ◽

Helger G. Yntema ◽

Reedik Mägi ◽

Reidar Andreson ◽

Andres Metspalu ◽

...

Keyword(s):

Autosomal Recessive ◽

Pathogenic Variants ◽

Specific Effects ◽

European Populations

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Molecular genetic diagnostics of Bardet-Biedl syndrome with an MPS-panel

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2021.03.26-35 ◽

2021 ◽

pp. 26-35

Author(s):

М.Д. Орлова ◽

П. Гундорова ◽

А.В. Поляков

Keyword(s):

Autosomal Recessive ◽

Molecular Genetic ◽

Autosomal Recessive Disorder ◽

Genetic Diagnostics ◽

Bardet Biedl Syndrome ◽

Pathogenic Variants ◽

Development Delay ◽

Molecular Genetic Diagnostics ◽

First Time

Синдром Барде-Бидля - аутосомно-рецессивное заболевание, характеризующееся ожирением, пигментной дегенерацией сетчатки, полидактилией, задержкой психоречевого развития и структурными повреждениями почек. В работе представлены результаты применения МПС-панели, включающей кодирующие последовательности и прилегающие интронные области 21 гена, ассоциированного с синдромом Барде-Бидля. Впервые была проведена молекулярно-генетическая диагностика в группе из сорока российских пациентов с синдромом Барде-Бидля из неродственных семей. В результате исследования удалось подтвердить диагноз молекулярно-генетическим методом у 40% пациентов (n=16). В генах BBS1, BBS7 и BBS10 встретились повторяющиеся варианты. Частота встречаемости патогенных и вероятно патогенных вариантов в генах BBS1 и BBS10 у российских пациентов соответствует зарубежным данным. Варианты в гене BBS7 встретились у пяти человек, у четырех из них был обнаружен патогенный вариант c.1967_1968delTAinsC, не встречающийся в других популяциях. Результаты, представленные в статье, показывают значительный вклад в заболеваемость синдромом Барде-Бидля в российской популяции патогенных вариантов в гене BBS7. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by obesity, retinitis pigmentosa, polydactyly, development delay, and structural kidney defects. This study shows the results of using an MPS panel that includes coding sequences and intronic areas of 21 genes associated with Bardet-Biedl syndrome. For the first time molecular genetic testing has been provided for the group of 40 Russian patiens with Bardet-Biedl syndrome from unrelated families. As a result of the testing, diagnoses were confirmed for 40% of the patients (n=16). The genes BBS1, BBS7, BBS10 had recurrent variants. The frequency of pathogenic and likely pathogenic variants in the genes BBS1 and BBS10 among Russian patients matches the research data in other countries. Variants in the BBS7 gene were found for five people, four of them had a pathogenic variant c.1967_1968delTAinsC, which is not present among other populations. Results provided in this article show the significant role of pathogenic variants in the BBS7 gene in patients with Bardet-Biedl syndrome in Russian population.

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Identification of candidate gene FAM183A and novel pathogenic variants in known genes: High genetic heterogeneity for autosomal recessive intellectual disability

PLoS ONE ◽

10.1371/journal.pone.0208324 ◽

2018 ◽

Vol 13 (11) ◽

pp. e0208324 ◽

Cited By ~ 5

Author(s):

Megan McSherry ◽

Katherine E. Masih ◽

Nursel H. Elcioglu ◽

Pelin Celik ◽

Ozge Balci ◽

...

Keyword(s):

Intellectual Disability ◽

Candidate Gene ◽

Genetic Heterogeneity ◽

Autosomal Recessive ◽

Pathogenic Variants

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Atypical Presentation of Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency with Developmental Epileptic Encephalopathy

Journal of Pediatric Epilepsy ◽

10.1055/s-0041-1723768 ◽

2021 ◽

Author(s):

Francesca Marchese ◽

Elena Faedo ◽

Maria Stella Vari ◽

Patrizia Bergonzini ◽

Michele Iacomino ◽

...

Keyword(s):

Amino Acid ◽

Autosomal Recessive ◽

Epileptic Encephalopathy ◽

Dopa Decarboxylase ◽

Acid Decarboxylase ◽

Homozygous Mutation ◽

Amino Acid Decarboxylase ◽

Pathogenic Variants ◽

Neurological Features ◽

Decarboxylase Deficiency

AbstractAromatic L-amino acid decarboxylase (AADC) deficiency is an autosomal recessive metabolic disorder resulting from disease-causing pathogenic variants of the dopa decarboxylase (DDC) gene. The neurological features of AADC deficiency include early-onset hypotonia, oculogyric crises, ptosis, dystonia, hypokinesia, impaired development, and autonomic dysfunction. We report a patient with genetically confirmed AADC deficiency presenting with developmental epileptic encephalopathy (DEE). We report a boy with severe intractable epileptic spasms and DEE. The patient was evaluated for cognitive and neurologic impairment. Exome sequencing revealed a homozygous mutation (NM_000790.4:c.121C > A; p.Leu41Met) in the DDC gene. This case expands the clinical spectrum of AADC deficiency and strengthens the association between dopa decarboxylase deficiency and epilepsy. Additional studies are warranted to clarify the mechanisms linking dopa decarboxylase dysfunction to DEE.

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