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

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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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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Prevalence of CYP17A1 gene mutations in 17α-hydroxylase deficiency in the Chinese Han population

Clinical Hypertension ◽

10.1186/s40885-019-0128-6 ◽

2019 ◽

Vol 25 (1) ◽

Cited By ~ 1

Author(s):

Menglin Wang ◽

Hao Wang ◽

Haiying Zhao ◽

Ling Li ◽

Min Liu ◽

...

Keyword(s):

Autosomal Recessive ◽

Gene Mutations ◽

Autosomal Recessive Disorder ◽

Chinese Han ◽

Hydroxylase Deficiency ◽

Case Presentation ◽

Chinese Populations ◽

Pathogenic Variants ◽

Cytochrome P450 Family ◽

Chinese Girls

Abstract Background 17α-hydroxylase deficiency is a rare autosomal recessive disorder caused by mutations in the cytochrome P450 family 17 subfamily A member 1 gene. The major clinical presentation includes hypertension, hypokalemia, male pseudohermaphroditism and female gonadal dysplasia. Hundreds of pathogenic variants have been reported in this disorder, and some common mutations were found to be race-specific. Case presentation In this study, we reported 5 Chinese girls with 17α-hydroxylase deficiency from Henan Province. The patients all came to the hospital for hypertension, and they also presented with sexual infantilism. The average age of the patients was 14 years old, ranging from 12 to 17 years old. They all had reduced blood cortisol, estradiol (E2), and testosterone (TESTO) and increased adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). They all had the appearance of females; however, three of the chromosome karyotypes were 46XX, and two were 46XY. Conclusions All of the patients carried a mutation on the 329 amino acid of CYP17A1 exon 6. By summarizing the currently known pathogenic mutations of 17α-hydroxylase deficiency, we demonstrated the prevalence of these gene mutations in Chinese Han and non-Chinese populations.

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

Hormone Research in Paediatrics ◽

10.1159/000514280 ◽

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

Introduction: 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 PLK4 gene, 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. Case Presentation: Here, we describe 2 siblings of different sex from Equatorial Guinea harboring a homozygous frameshift mutation in PLK4 (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. Discussion/Conclusion: Biallelic variants in PLK4 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.

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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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Warmblood fragile foal syndrome causative single nucleotide polymorphism frequency in horses in Ireland

Irish Veterinary Journal ◽

10.1186/s13620-021-00206-1 ◽

2021 ◽

Vol 74 (1) ◽

Author(s):

Áine Rowe ◽

Sharon Flanagan ◽

Gerald Barry ◽

Lisa M. Katz ◽

Elizabeth A. Lane ◽

...

Keyword(s):

Autosomal Recessive ◽

Scientific Literature ◽

Genetic Test ◽

Low Frequency ◽

Autosomal Recessive Disorder ◽

Causative Mutation ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Hair Samples ◽

Heterozygous Carriers

Abstract Background Warmblood Fragile Foal Syndrome (WFFS) is an autosomal recessive disorder caused by a mutation in the procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1) gene. Homozygosity for the mutation results in defective collagen synthesis which clinically manifests as the birth of non viable or still born foals with abnormally fragile skin. While the mutation has been identified in non Warmblood breeds including the Thoroughbred, to date all homozygous clinically affected cases reported in the scientific literature are Warmblood foals. The objective of this study was to investigate the carrier frequency of the mutation in the Thoroughbred and sport horse populations in Ireland. Methods A test was developed at the UCD School of Veterinary Medicine using real-time PCR to amplify the PLOD1 gene c.2032G > A variant. A subset of the samples was also submitted to an external laboratory with a licensed commercial WFFS genetic test. Results Warmblood Fragile Foal Syndrome genotyping was performed on hair samples from 469 horses representing 6 different breeds. Six of 303 (1.98%) sport horses tested and three of 109 (2.75%) Thoroughbreds tested were heterozygous for the WFFS polymorphism (N/WFFS). The WFFS polymorphism was not identified in the Standardbred, Cob, Connemara, or other pony breeds. Conclusions The study identified a low frequency of the WFFS causative mutation in sport horses and Thoroughbreds in Ireland, highlighting the importance of WFFS genetic testing in order to identify phenotypically normal heterozygous carriers and to prevent the birth of nonviable foals.

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

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2016-0280 ◽

2017 ◽

Vol 30 (1) ◽

Cited By ~ 8

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

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A Novel Claudinopathy Based on Claudin-10 Mutations

International Journal of Molecular Sciences ◽

10.3390/ijms20215396 ◽

2019 ◽

Vol 20 (21) ◽

pp. 5396 ◽

Cited By ~ 1

Author(s):

Susanne Milatz

Keyword(s):

Tight Junction ◽

Autosomal Recessive ◽

Autosomal Recessive Disorder ◽

Cation Channels ◽

Exocrine Glands ◽

The Past ◽

Pathogenic Variants ◽

Functional Relevance

Claudins are key components of the tight junction, sealing the paracellular cleft or composing size-, charge- and water-selective paracellular channels. Claudin-10 occurs in two major isoforms, claudin-10a and claudin-10b, which constitute paracellular anion or cation channels, respectively. For several years after the discovery of claudin-10, its functional relevance in men has remained elusive. Within the past two years, several studies appeared, describing patients with different pathogenic variants of the CLDN10 gene. Patients presented with dysfunction of kidney, exocrine glands and skin. This review summarizes and compares the recently published studies reporting on a novel autosomal-recessive disorder based on claudin-10 mutations.

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