Primary Dwarfism, Microcephaly, and Chorioretinopathy due to a PLK4 Mutation in Two Siblings

2020 ◽  
Vol 93 (9-10) ◽  
pp. 567-572
Author(s):  
Álvaro Martín-Rivada ◽  
Jesús Pozo-Román ◽  
María Güemes ◽  
Nelmar Valentina Ortiz-Cabrera ◽  
Luis A. Pérez-Jurado ◽  
...  
Keyword(s):  
Short Stature ◽  
Autosomal Recessive ◽  
Genetic Basis ◽  
Frameshift Mutation ◽  
Psychomotor Development ◽  
Facial Features ◽  
Loss Of Function ◽  
Case Presentation ◽  
Severe Intellectual Disability ◽  
Severe Short Stature

<b><i>Introduction:</i></b> Primary autosomal recessive microcephalies (MCPHs) are characterized by primary dwarfism with MCPH and may present delayed psychomotor development and visual impairment. Biallelic loss of function variants in the <i>PLK4</i> gene<i>,</i> which encodes the polo-like kinase 4 protein involved in centriole biogenesis, has been recently identified in several patients with MCPH and various ethnic backgrounds. <b><i>Case Presentation:</i></b> Here, we describe 2 siblings of different sex from Equatorial Guinea harboring a homozygous frameshift mutation in <i>PLK4</i> (c.1299_1303del, p.Phe433Leufs*6). A Seckel syndrome spectrum phenotype was present in both siblings, with short stature, severe MCPH, reduced brain volume, and distinctive facial features. They also presented severe intellectual disability, lissencephaly/pachygyria, subependymal heterotopia, and ophthalmological impairment. One of them suffered from deafness, and scoliosis was observed in the other. <b><i>Discussion/Conclusion:</i></b> Biallelic variants in <i>PLK4</i> lead to a syndrome where severe short stature, MCPH, and cognitive impairment are constant features. However, ocular, skeletal, and other neurological manifestations can vary upon the same genetic basis.

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

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.

scholarly journals Laron syndrome in three female siblings with the development of subclinical hypothyroidism and dyslipidemia in one case: first report of a Syrian family

2021 ◽  
Vol 2021 (9) ◽  
Author(s):  
Ahmad Chreitah ◽  
Kheria Hijazia ◽  
Leen Jamel Doya
Keyword(s):  
Short Stature ◽  
Subclinical Hypothyroidism ◽  
Autosomal Recessive ◽  
Index Case ◽  
Autosomal Recessive Disorder ◽  
Facial Features ◽  
Laron Syndrome ◽  
High Clinical Suspicion ◽  
Facial Phenotype ◽  
Severe Short Stature

ABSTRACT Laron syndrome (LS) is a rare autosomal recessive disorder characterized by dwarfism and typical facial phenotype. This report is the first to present three cases of Laron syndrome affecting three female siblings from Syria. The index case presented at age of 8.5 years with severe short stature: low level of Insulin-like growth factor 1 (IGF-1), elevated levels of fasting and post-stimulation growth hormone (GH), consistent with the diagnosis of Laron syndrome. At the age of 9.5 years, she developed non-autoimmune subclinical hypothyroidism treated with Levothyroxine, then she developed dyslipidemia at the age of 11.3 years. Later, we identified two female siblings of the patient with Laron syndrome. Laron syndrome is a rare genetic disease, reporting of new cases of this rare syndrome must encourage pediatricians to develop high clinical suspicion if faced with patients with very short stature and typical facial features.

scholarly journals Autosomal recessive chondrodysplasia with severe short stature caused by a biallelic COL10A1 variant

2017 ◽  
Vol 55 (6) ◽  
pp. 403-407 ◽  
Author(s):  
Noor ul Ain ◽  
Outi Makitie ◽  
Sadaf Naz
Keyword(s):  
Short Stature ◽  
Skeletal Dysplasia ◽  
In Silico ◽  
Autosomal Recessive ◽  
Limb Deformity ◽  
Mild Phenotype ◽  
Whole Exome ◽  
New Type ◽  
Severe Short Stature ◽  
Amino Acid Conservation

BackgroundHeterozygous mutations in COL10A1 underlie metaphyseal chondrodysplasia, Schmid type (MCDS), an autosomal dominant skeletal dysplasia.ObjectiveTo identify the causative variant in a large consanguineous Pakistani family with severe skeletal dysplasia and marked lower limb deformity.MethodsWhole exome sequencing was completed followed by Sanger sequencing to verify segregation of the identified variants. In silico variant pathogenicity predictions and amino acid conservation analyses were performed.ResultsA homozygous c.133 C>T (p.Pro45Ser) variant was identified in COL10A1 in all six severely affected individuals (adult heights 119–130 cm, mean ~−6.33 SD). The individuals heterozygous for the variant had mild phenotype of short stature (adult heights 140–162 cm, mean ~−2.15 SD) but no apparent skeletal deformities. The variant was predicted to be pathogenic by in silico prediction tools and was absent from public databases and hundred control chromosomes. Pro45 is conserved in orthologues and is located in the non-collagenous 2 domain of COL10A1, variants of which have never been associated with skeletal dysplasia.ConclusionsThis first report of individuals with a homozygous variant in COL10A1 defines a new type of autosomal recessive skeletal dysplasia. The observations in COL10A1 variant carriers suggest a phenotypic overlap between the mildest forms of MCDS and idiopathic short stature.

Long-term response to growth hormone therapy in a patient with short stature caused by a novel heterozygous mutation in NPR2

2017 ◽  
Vol 30 (1) ◽  
Author(s):  
Gabriela A. Vasques ◽  
Alfonso Hisado-Oliva ◽  
Mariana F.A. Funari ◽  
Antonio M. Lerario ◽  
Elisangela P.S. Quedas ◽  
...  
Keyword(s):  
Short Stature ◽  
Growth Velocity ◽  
Fat Distribution ◽  
Heterozygous Mutation ◽  
First Year ◽  
Loss Of Function ◽  
Nasal Bridge ◽  
Case Presentation ◽  
Hormonal Evaluation

AbstractBackground:Heterozygous loss-of-function mutations in the natriuretic peptide receptor B gene (Case presentation:The proband was a healthy boy who presented at the age of 5.1 years with familial short stature (height SDS of −3.1). He had a prominent forehead, a depressed nasal bridge, centripetal fat distribution and a high-pitched voice resembling that of children with GH deficiency. His hormonal evaluation showed low insulin-like growth factor-1 (IGF-1) but a normal GH peak at a stimulation test. During the first year of rhGH treatment, his growth velocity increased from 3.4 to 10.4 cm/year (height SDS change of +1.1). At the last visit, he was 8.8 years old and still on treatment, his growth velocity was 6.4 cm/year and height SDS was −1.8.Results:We identified through exome sequencing a novel heterozygous loss-of-functionConclusions:This case reveals a novel heterozygous loss-of-function

scholarly journals Parkin truncating variants result in a loss-of-function phenotype

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Mariana Santos ◽  
Sara Morais ◽  
Conceição Pereira ◽  
Jorge Sequeiros ◽  
Isabel Alonso
Keyword(s):  
Autosomal Recessive ◽  
Genetic Basis ◽  
Neurodegenerative Disorder ◽  
Causative Role ◽  
Loss Of Function ◽  
Portuguese Population ◽  
Juvenile Onset ◽  
Ubiquitin E3 Ligase ◽  
Spanish Populations ◽  
Common Neurodegenerative Disorder

Abstract Parkinson disease (PD) is the second most common neurodegenerative disorder. Most cases of PD are sporadic, while 5–10% have a known genetic basis. Variants in the PARK2 gene are the most frequent cause of autosomal recessive juvenile-onset PD. PARK2 encodes parkin, a multi-domain protein that functions as an ubiquitin E3 ligase. Numerous variants spanning all parkin domains have been identified, although the pathogenic relevance for several of those remains unclear. In this study, we aimed to functionally characterize two truncating parkin variants: N52Mfs*29, which is highly prevalent in the Portuguese and Spanish populations, and L358Rfs*77, recently identified in the Portuguese population. Our results indicate that both variants are prematurely degraded by the proteasome, even though proteins levels are still moderate. We also showed that they are aggregation-prone and lead to mislocalized parkin. Interestingly, the L358Rfs*77 variant is mislocalized to the nucleus, which was never reported for parkin variants. While N52Mfs*29 impaired self-ubiquitination activity, the L358Rfs*77 variant seemed to retain it. Both variants, however, fail to ubiquitinate p62 substrate and did not relocalize to depolarized mitochondria. Therefore, we conclude that parkin truncating variants cause loss of parkin function, thus showing their causative role in PD pathogenesis.

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

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.

scholarly journals Novel variants identified in CKAP2L in two siblings with Filippi Syndrome

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.

scholarly journals A Novel Mutation in the VPS13B Gene in a Cohen Syndrome Patient with Positive Antiphospholipid Antibodies

2021 ◽  
Vol 2021 ◽  
pp. 1-3
Author(s):  
Roghayeh Dehghan ◽  
Mahdiyeh Behnam ◽  
Alireza Moafi ◽  
Mansoor Salehi
Keyword(s):  
Antiphospholipid Antibodies ◽  
Autosomal Recessive ◽  
Novel Mutation ◽  
Mental Deficiency ◽  
Autosomal Recessive Disorder ◽  
Facial Features ◽  
Loss Of Function ◽  
Cohen Syndrome ◽  
Mild Anemia ◽  
Homozygous Nonsense Mutation

Cohen syndrome is an autosomal recessive disorder with the primary symptoms of mental deficiency, progressive retinopathy, hypotonia, microcephaly, obesity of midchildhood onset, intermittent neutropenia, and dysmorphic facial features. The syndrome has high phenotypic heterogeneity and is caused by loss-of-function mutations in the VPS13B gene. Here, we introduce a novel homozygous nonsense mutation (c.8698G > T, p.E2900X) in the VPS13B gene in an 11-year-old Iranian boy with major symptoms of Cohen syndrome. He also had mild anemia accompanied by positive antiphospholipid antibodies, the latter has never been previously reported in Cohen syndrome.

scholarly journals Heterozygous NPR2 Mutation in Two Family Members with Short Stature and Skeletal Dysplasia

2018 ◽  
Vol 2018 ◽  
pp. 1-4 ◽  
Author(s):  
Marianne Jacob ◽  
Surabhi Menon ◽  
Christina Botti ◽  
Ian Marshall
Keyword(s):  
Short Stature ◽  
Natriuretic Peptide ◽  
Skeletal Dysplasia ◽  
Endochondral Ossification ◽  
Recombinant Human Growth Hormone ◽  
Human Growth ◽  
Loss Of Function ◽  
Peptide Receptor ◽  
Radiological Features ◽  
Severe Short Stature

Endochondral ossification at the level of the growth plate, an essential process involved in longitudinal growth, is regulated by hormonal and local factors including C-type natriuretic peptide and its receptor, natriuretic peptide receptor B. Biallelic loss-of-function mutations in the NPR2 gene, which encodes this receptor, cause acromesomelic dysplasia, Maroteaux type (AMDM), a skeletal dysplasia characterized by severe short stature and disproportionate shortening of limbs. Heterozygous NPR2 mutations have been reported in patients previously classified with idiopathic short stature (ISS). We report the presentation of a 7-year-old girl and her mother with short stature, both of whom were identified with the same NPR2 mutation, and who demonstrated clinical and radiological features consistent with a skeletal dysplasia. We also report the patient’s response to recombinant human growth hormone (rhGH) over a 2-year period. We encourage clinicians who evaluate children with ISS to consider genetic testing, particularly when the presentation is associated with features suggestive of a skeletal dysplasia.

scholarly journals Novel mutations in PDE6A and CDHR1 cause retinitis pigmentosa in Pakistani families

2021 ◽  
Vol 14 (12) ◽  
pp. 1843-1851
Author(s):  
Muhammad Dawood ◽  
◽  
Taj Ud Din ◽  
Irfan Ullah Shah ◽  
Niamat Khan ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Autosomal Recessive ◽  
Genetic Basis ◽  
Frameshift Mutation ◽  
Splice Site Mutation ◽  
Novel Mutations ◽  
Site Mutation ◽  
Whole Exome ◽  
Potential Pathogenicity ◽  
Pakistani Families

AIM: To investigate the genetic basis of autosomal recessive retinitis pigmentosa (arRP) in two consanguineous/ endogamous Pakistani families. METHODS: Whole exome sequencing (WES) was performed on genomic DNA samples of patients with arRP to identify disease causing mutations. Sanger sequencing was performed to confirm familial segregation of identified mutations, and potential pathogenicity was determined by predictions of the mutations’ functions. RESULTS: A novel homozygous frameshift mutation [NM_000440.2:c.1054delG, p. (Gln352Argfs*4); Chr5:g.149286886del (GRCh37)] in the PDE6A gene in an endogamous family and a novel homozygous splice site mutation [NM_033100.3:c.1168-1G>A, Chr10:g.85968484G>A (GRCh37)] in the CDHR1 gene in a consanguineous family were identified. The PDE6A variant p. (Gln352Argfs*4) was predicted to be deleterious or pathogenic, whilst the CDHR1 variant c.1168-1G>A was predicted to result in potential alteration of splicing. CONCLUSION: This study expands the spectrum of genetic variants for arRP in Pakistani families.

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