Expanding the Spectrum of Neurological Manifestations in Cutis Laxa, Autosomal Recessive, Type IIIA

AbstractCutis laxa is a heterogeneous group of diseases, characterized by abundant and wrinkled skin and a variable degree of intellectual disability. Cutis laxa, autosomal recessive, type IIIA and autosomal dominant 3 syndromes are caused by autosomal recessive or de novo pathogenic variants in ALDH18A1. Autosomal recessive variants are known to lead to the most severe neurological phenotype, and very few patients have been described.We describe a 13-month-old patient with cutis laxa, autosomal recessive, type IIIA, with an extremely severe phenotype, including novel neurological findings. This description enlarges the neurological spectrum associated to cutis laxa, autosomal recessive, type IIIA, and provides an additional description of this syndrome.

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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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Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic

Frontiers in Genetics ◽

10.3389/fgene.2021.697549 ◽

2021 ◽

Vol 12 ◽

Author(s):

Youn Hee Jee ◽

Mariam Gangat ◽

Olga Yeliosof ◽

Adrian G. Temnycky ◽

Selena Vanapruks ◽

...

Keyword(s):

Pituitary Gland ◽

Autosomal Recessive ◽

De Novo ◽

Genetic Component ◽

Control Group ◽

Complete Penetrance ◽

Pathogenic Variants ◽

Testing Approach ◽

Congenital Hypopituitarism ◽

Gland Development

PurposeCongenital hypopituitarism usually occurs sporadically. In most patients, the etiology remains unknown.MethodsWe studied 13 children with sporadic congenital hypopituitarism. Children with non-endocrine, non-familial idiopathic short stature (NFSS) (n = 19) served as a control group. Exome sequencing was performed in probands and both unaffected parents. A burden testing approach was used to compare the number of candidate variants in the two groups.ResultsFirst, we assessed the frequency of rare, predicted-pathogenic variants in 42 genes previously reported to be associated with pituitary gland development. The average number of variants per individual was greater in probands with congenital hypopituitarism than those with NFSS (1.1 vs. 0.21, mean variants/proband, P = 0.03). The number of probands with at least 1 variant in a pituitary-associated gene was greater in congenital hypopituitarism than in NFSS (62% vs. 21%, P = 0.03). Second, we assessed the frequency of rare, predicted-pathogenic variants in the exome (to capture undiscovered causes) that were inherited in a fashion that could explain the sporadic occurrence of the proband’s condition with a monogenic etiology (de novo mutation, autosomal recessive, or X-linked recessive) with complete penetrance. There were fewer monogenic candidates in the probands with congenital hypopituitarism than those with NFSS (1.3 vs. 2.5 candidate variants/proband, P = 0.024). We did not find any candidate variants (0 of 13 probands) in genes previously reported to explain the phenotype in congenital hypopituitarism, unlike NFSS (8 of 19 probands, P = 0.01).ConclusionOur findings provide evidence that the etiology of sporadic congenital hypopituitarism has a major genetic component but may be infrequently monogenic with full penetrance, suggesting a more complex etiology.

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Identification of a Novel 19-bp Deletion Mutation in LTBP4 Using Exome Sequencing in Two Siblings with Autosomal Recessive Cutis Laxa Type 1C

Journal of Pediatric Genetics ◽

10.1055/s-0039-1698806 ◽

2019 ◽

Vol 09 (02) ◽

pp. 125-131 ◽

Cited By ~ 1

Author(s):

Neerja Gupta ◽

Nitika Langeh ◽

Aparajit Sridharan ◽

Madhulika Kabra

Keyword(s):

Base Pair ◽

Autosomal Recessive ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Homozygous Deletion ◽

Cutis Laxa ◽

Type I ◽

Recessive Type ◽

Single Base Pair ◽

Biallelic Mutations

AbstractAutosomal recessive type I cutis laxa is genetically heterogeneous. Biallelic mutations in latent transforming growth factor β-binding protein 4 (LTBP4; MIM*604710) lead to type 1C cutis laxa due to nonsense, frameshift, single base pair indels, or duplication mutations. In this report, we describe the first Indian family with cutis laxa as a result of a novel 19 base pair homozygous deletion leading to premature termination of short isoform LTBP-4S.

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Cell-based analysis of CAD variants identifies individuals likely to benefit from uridine therapy

Genetics in Medicine ◽

10.1038/s41436-020-0833-2 ◽

2020 ◽

Vol 22 (10) ◽

pp. 1598-1605 ◽

Cited By ~ 3

Author(s):

Francisco del Caño-Ochoa ◽

Bobby G. Ng ◽

Malak Abedalthagafi ◽

Mohammed Almannai ◽

Ronald D. Cohn ◽

...

Keyword(s):

Autosomal Recessive ◽

Clinical Presentation ◽

De Novo ◽

Clinical Phenotype ◽

Transient Transfection ◽

Missense Variants ◽

De Novo Biosynthesis ◽

Pathogenic Variants ◽

Large Size ◽

A Cell

Abstract Purpose Pathogenic autosomal recessive variants in CAD, encoding the multienzymatic protein initiating pyrimidine de novo biosynthesis, cause a severe inborn metabolic disorder treatable with a dietary supplement of uridine. This condition is difficult to diagnose given the large size of CAD with over 1000 missense variants and the nonspecific clinical presentation. We aimed to develop a reliable and discerning assay to assess the pathogenicity of CAD variants and to select affected individuals that might benefit from uridine therapy. Methods Using CRISPR/Cas9, we generated a human CAD-knockout cell line that requires uridine supplements for survival. Transient transfection of the knockout cells with recombinant CAD restores growth in absence of uridine. This system determines missense variants that inactivate CAD and do not rescue the growth phenotype. Results We identified 25 individuals with biallelic variants in CAD and a phenotype consistent with a CAD deficit. We used the CAD-knockout complementation assay to test a total of 34 variants, identifying 16 as deleterious for CAD activity. Combination of these pathogenic variants confirmed 11 subjects with a CAD deficit, for whom we describe the clinical phenotype. Conclusions We designed a cell-based assay to test the pathogenicity of CAD variants, identifying 11 CAD-deficient individuals who could benefit from uridine therapy.

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Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland

Human Genetics ◽

10.1007/s00439-021-02268-1 ◽

2021 ◽

Author(s):

Irma Järvelä ◽

Tuomo Määttä ◽

Anushree Acharya ◽

Juha Leppälä ◽

Shalini N. Jhangiani ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Autosomal Recessive ◽

Autosomal Dominant ◽

De Novo ◽

Uniparental Disomy ◽

Molecular Testing ◽

Potential Candidate ◽

Founder Population ◽

Id Genes

AbstractThe genetics of autosomal recessive intellectual disability (ARID) has mainly been studied in consanguineous families, however, founder populations may also be of interest to study intellectual disability (ID) and the contribution of ARID. Here, we used a genotype-driven approach to study the genetic landscape of ID in the founder population of Finland. A total of 39 families with syndromic and non-syndromic ID were analyzed using exome sequencing, which revealed a variant in a known ID gene in 27 families. Notably, 75% of these variants in known ID genes were de novo or suspected de novo (64% autosomal dominant; 11% X-linked) and 25% were inherited (14% autosomal recessive; 7% X-linked; and 4% autosomal dominant). A dual molecular diagnosis was suggested in two families (5%). Via additional analysis and molecular testing, we identified three cases with an abnormal molecular karyotype, including chr21q22.12q22.2 uniparental disomy with a mosaic interstitial 2.7 Mb deletion covering DYRK1A and KCNJ6. Overall, a pathogenic or likely pathogenic variant was identified in 64% (25/39) of the families. Last, we report an alternate inheritance model for 3 known ID genes (UBA7, DDX47, DHX58) and discuss potential candidate genes for ID, including SYPL1 and ERGIC3 with homozygous founder variants and de novo variants in POLR2F and DNAH3. In summary, similar to other European populations, de novo variants were the most common variants underlying ID in the studied Finnish population, with limited contribution of ARID to ID etiology, though mainly driven by founder and potential founder variation in the latter case.

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A de novo STUB1 variant associated with an early adult-onset multisystemic ataxia phenotype

Journal of Neurology ◽

10.1007/s00415-021-10524-7 ◽

2021 ◽

Author(s):

David Mengel ◽

Andreas Traschütz ◽

Selina Reich ◽

Alejandra Leyva-Gutiérrez ◽

Friedemann Bender ◽

...

Keyword(s):

Early Onset ◽

Autosomal Recessive ◽

Autosomal Dominant ◽

De Novo ◽

Family Members ◽

Start Codon ◽

Mrna Levels ◽

Adult Onset ◽

Loss Of Function ◽

Autosomal Dominant Disorder

Abstract Background Biallelic STUB1 variants are a well-established cause of autosomal-recessive early-onset multisystemic ataxia (SCAR16). Evidence for STUB1 variants causing autosomal-dominant ataxia (SCA48) so far largely relies on segregation data in larger families. Presenting the first de novo occurrence of a heterozygous STUB1 variant, we here present additional qualitative evidence for STUB1-disease as an autosomal-dominant disorder. Methods Whole exome sequencing on an index patient with sporadic early-onset ataxia, followed by Sanger sequencing in all family members, was used to identify causative variants as well as to rule out alternative genetic hits and intronic STUB1 variants. STUB1 mRNA and protein levels in PBMCs in all family members were analysed using qRT-PCR and Western Blot. Results A previously unreported start-lost loss-of-function variant c.3G>A in the start codon of STUB1 was identified in the index case, occurring de novo and without evidence for a second (potentially missed) variant (e.g., intronic or copy number) in STUB1. The patient showed an early adult-onset multisystemic ataxia complicated by spastic gait disorder, distal myoclonus and cognitive dysfunction, thus closely mirroring the systems affected in autosomal-recessive STUB1-associated disease. In line with the predicted start-lost effect of the variant, functional investigations demonstrated markedly reduced STUB1 protein expression in PBMCs, whereas mRNA levels were intact. Conclusion De novo occurrence of the loss-of-function STUB1 variant in our case with multisystemic ataxia provides a qualitatively additional line of evidence for STUB1-disease as an autosomal-dominant disorder, in which the same neurological systems are affected as in its autosomal-recessive counterpart. Moreover, this finding adds support for loss-of-function as a mechanism underlying autosomal-dominant STUB1-disease, thus mirroring its autosomal-recessive counterpart also in terms of the underlying mutational mechanism.

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Parental segregation study reveals rare benign and likely benign variants in a Brazilian cohort of rare diseases

10.22541/au.163255745.52740737/v1 ◽

2021 ◽

Author(s):

Caio Robledo Quaio ◽

Jose Ricardo Magliocco Ceroni ◽

Murilo Castro Cervato ◽

Helena Strelow Thurow ◽

Caroline Monaco Moreira ◽

...

Keyword(s):

Rare Diseases ◽

Segregation Analysis ◽

Autosomal Dominant ◽

Rare Variants ◽

De Novo ◽

Molecular Data ◽

Autosomal Dominant Inheritance ◽

Dominant Inheritance ◽

Pathogenic Variants ◽

Genomic Studies

Genomic studies may generate massive amounts of data, bringing interpretation challenges. Efforts for the differentiation of benign and pathogenic variants gain importance. In this article, we used segregation analysis and other molecular data to reclassify to benign or likely benign several rare clinically curated variants of autosomal dominant inheritance from a cohort of 500 Brazilian patients with rare diseases. This study included only symptomatic patients who had undergone molecular investigation with exome sequencing for suspected diseases of genetic etiology. Variants clinically suspected as the causative etiology and harbored by genes associated with highly-penetrant conditions of autosomal dominant inheritance underwent Sanger confirmation in the proband and inheritance pattern determination because a “de novo” event was expected. Among all 327 variants studied, 321 variants were inherited from asymptomatic parents. Considering segregation analysis, we have reclassified 51 rare variants as benign (n=51) and 211 as likely benign (n=211). In our study, the inheritance of a highly penetrant variant expected to be de novo for pathogenicity assumption was considered as a non-segregation and, therefore, a key step for benign or likely benign classification. Studies like ours may help to identify rare benign variants and improve the correct interpretation of genetic findings.

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Hereditary spastic paraplegia:Pathogenesis and pathophysiology

NATIONAL JOURNAL OF NEUROLOGY ◽

10.28942/nnj.v1i5.105 ◽

2018 ◽

pp. 1-13

Author(s):

Akgun Olmez ◽

Haluk Topaloglu

Keyword(s):

Genetic Testing ◽

Corpus Callosum ◽

Hereditary Spastic Paraplegia ◽

Autosomal Recessive ◽

Autosomal Dominant ◽

Spastic Paraplegia ◽

Thin Corpus Callosum ◽

Hereditary Spastic Paraplegias ◽

Recessive Type ◽

Mitochondrial Functions

Hereditary spastic paraplegias constitute a larger group of disorders than expected. Autosomal dominant types are mainly composed of SPAST, Atlastin (SPG3A) and REEP1 Genetic testing is suggested mainly for these genes. The most common autosomal recessive type is SPG11, hereditary spastic paraplegia with thin corpus callosum, but SPG15 shares the same clinical features with SPG11. Genetic testing should be done for both if thin corpus callosum is present in patients. How different genes with many different biological functions, including axonal transport, mitochondrial functions, fatty acid and cholesterol pathways and DNA repair defects, cause hereditary spastic paraplegia is still unknown.

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A Japanese Patient with Genitopatellar Syndrome Transiently Presenting with Cardiac Intramural Cavity during the Neonatal Period

Case Reports in Genetics ◽

10.1155/2020/1731720 ◽

2020 ◽

Vol 2020 ◽

pp. 1-5

Author(s):

Kiichi Takahashi ◽

Hiroyuki Adachi ◽

Manatomo Toyono ◽

Masato Ito ◽

Akie Kato ◽

...

Keyword(s):

Autosomal Dominant ◽

De Novo ◽

Heart Defects ◽

Ductus Arteriosus ◽

Renal Cysts ◽

Ventricular Septal Defects ◽

Autosomal Dominant Disorder ◽

Septal Defects ◽

Pathogenic Variants

Genitopatellar syndrome (GPS) is a rare autosomal dominant disorder caused by de novo pathogenic variants in the KAT6B gene. It is characterized by genital abnormalities, patellar hypoplasia/agenesis, flexion contractures of the hips and knees, corpus callosum agenesis with microcephaly, and hydronephrosis and/or multiple renal cysts. More than half of patients with GPS have congenital heart defects, mostly atrial and/or ventricular septal defects, patent foramen ovale, and patent ductus arteriosus. We report a case of a Japanese neonate with a de novo heterozygous c.3769_3772delTCTA pathogenic variant in the KAT6B gene who presented with a cardiac intramural cavity of the ventricular septum at birth. The cavity unexpectedly disappeared at 1 month of age, but trabecular septal thinning and flash remained. The features of the cavity were not consistent with those of congenital ventricular diverticulum or aneurysm, and its identity and prognosis are still unclear. Because patients with GPS may exhibit various forms of cardiac malformation, careful cardiac examination and follow-up are required from birth in cases of suspected GPS.

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