Developmental delay, intellectual disability, short stature, subglottic stenosis, hearing impairment, onychodysplasia of the index fingers, and distinctive facial features: A newly reported autosomal recessive syndrome

Abstract Background Large-scale genomic analyses have provided insight into the genetic complexity of short stature (SS); however, only a portion of genetic causes have been identified. In this study, we identified disease-causing mutations in a cohort of Korean patients with suspected syndromic SS by targeted exome sequencing (TES). Methods Thirty-four patients in South Korea with suspected syndromic disorders based on abnormal growth and dysmorphic facial features, developmental delay, or accompanying anomalies were enrolled in 2018–2020 and evaluated by TES. Results For 17 of 34 patients with suspected syndromic SS, a genetic diagnosis was obtained by TES. The mean SDS values for height, IGF-1, and IGFBP-3 for these 17 patients were − 3.27 ± 1.25, − 0.42 ± 1.15, and 0.36 ± 1.31, respectively. Most patients displayed distinct facial features (16/17) and developmental delay or intellectual disability (12/17). In 17 patients, 19 genetic variants were identified, including 13 novel heterozygous variants, associated with 15 different genetic diseases, including many inherited rare skeletal disorders and connective tissue diseases (e.g., cleidocranial dysplasia, Hajdu–Cheney syndrome, Sheldon–Hall, acromesomelic dysplasia Maroteaux type, and microcephalic osteodysplastic primordial dwarfism type II). After re-classification by clinical reassessment, including family member testing and segregation studies, 42.1% of variants were pathogenic, 42.1% were likely pathogenic variant, and 15.7% were variants of uncertain significance. Ultra-rare diseases accounted for 12 out of 15 genetic diseases (80%). Conclusions A high positive result from genetic testing suggests that TES may be an effective diagnostic approach for patients with syndromic SS, with implications for genetic counseling. These results expand the mutation spectrum for rare genetic diseases related to SS in Korea.

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Matching Two Independent Cohorts ValidatesDPH1as a Gene Responsible for Autosomal Recessive Intellectual Disability with Short Stature, Craniofacial, and Ectodermal Anomalies

Human Mutation ◽

10.1002/humu.22843 ◽

2015 ◽

Vol 36 (10) ◽

pp. 1015-1019 ◽

Cited By ~ 19

Author(s):

Catrina M. Loucks ◽

Jillian S. Parboosingh ◽

Ranad Shaheen ◽

Francois P. Bernier ◽

D. Ross McLeod ◽

...

Keyword(s):

Intellectual Disability ◽

Short Stature ◽

Autosomal Recessive

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Biallelic variants in PSMB1 encoding the proteasome subunit β6 cause impairment of proteasome function, microcephaly, intellectual disability, developmental delay and short stature

Human Molecular Genetics ◽

10.1093/hmg/ddaa032 ◽

2020 ◽

Vol 29 (7) ◽

pp. 1132-1143 ◽

Cited By ~ 2

Author(s):

Muhammad Ansar ◽

Frédéric Ebstein ◽

Hayriye Özkoç ◽

Sohail A Paracha ◽

Justyna Iwaszkiewicz ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Autosomal Recessive ◽

Brain Size ◽

Autosomal Recessive Disorders ◽

Proteasome Subunit ◽

Pathogenic Variants ◽

The Family ◽

Proteasome Subunits ◽

Recessive Disorders

Abstract The molecular cause of the majority of rare autosomal recessive disorders remains unknown. Consanguinity due to extensive homozygosity unravels many recessive phenotypes and facilitates the detection of novel gene-disease links. Here, we report two siblings with phenotypic signs, including intellectual disability (ID), developmental delay and microcephaly from a Pakistani consanguineous family in which we have identified homozygosity for p(Tyr103His) in the PSMB1 gene (Genbank NM_002793) that segregated with the disease phenotype. PSMB1 encodes a β-type proteasome subunit (i.e. β6). Modeling of the p(Tyr103His) variant indicates that this variant weakens the interactions between PSMB1/β6 and PSMA5/α5 proteasome subunits and thus destabilizes the 20S proteasome complex. Biochemical experiments in human SHSY5Y cells revealed that the p(Tyr103His) variant affects both the processing of PSMB1/β6 and its incorporation into proteasome, thus impairing proteasome activity. CRISPR/Cas9 mutagenesis or morpholino knock-down of the single psmb1 zebrafish orthologue resulted in microcephaly, microphthalmia and reduced brain size. Genetic evidence in the family and functional experiments in human cells and zebrafish indicates that PSMB1/β6 pathogenic variants are the cause of a recessive disease with ID, microcephaly and developmental delay due to abnormal proteasome assembly.

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Bi-allelic Variants in IQSEC1 Cause Intellectual Disability, Developmental Delay, and Short Stature

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2019.09.013 ◽

2019 ◽

Vol 105 (5) ◽

pp. 907-920 ◽

Cited By ~ 4

Author(s):

Muhammad Ansar ◽

Hyung-lok Chung ◽

Ali Al-Otaibi ◽

Mohammad Nael Elagabani ◽

Thomas A. Ravenscroft ◽

...

Keyword(s):

Intellectual Disability ◽

Short Stature ◽

Developmental Delay ◽

Allelic Variants

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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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Microtriplication of 11q24.1: a highly recognisable phenotype with short stature, distinctive facial features, keratoconus, overweight, and intellectual disability

Journal of Medical Genetics ◽

10.1136/jmedgenet-2011-100008 ◽

2011 ◽

Vol 48 (9) ◽

pp. 635-639 ◽

Cited By ~ 6

Author(s):

C. Beneteau ◽

E. Landais ◽

M. Doco-Fenzy ◽

C. Gavazzi ◽

C. Philippe ◽

...

Keyword(s):

Intellectual Disability ◽

Short Stature ◽

Facial Features

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Challenges of Rehabilitation Interventions in Beaulieu-boycott-innes Syndrome: A Case Report

Iranian Rehabilitation Journal ◽

10.32598/irj.18.4.100.7 ◽

2020 ◽

Vol 18 (4) ◽

pp. 503-506

Author(s):

Masoud Gharib ◽

◽

Roshanak Vameghi ◽

Mohsen Fallahi ◽

◽

...

Keyword(s):

Developmental Delay ◽

Autosomal Recessive ◽

Autosomal Recessive Disorder ◽

Facial Features ◽

Secondary Complications ◽

Neurodevelopmental Delay ◽

Cognitive Interventions ◽

Iranian Children

Beaulieu-Boycott-Innes syndrome (BBIS), an autosomal recessive disorder, is characterized by dysmorphic facial features and developmental delay. In this case study, we used the age and stages questionnaire 2 (ASQ-2) to assess the developmental status of an Iranian 20-month-old girl displaying a complex BBIS phenotype. Rehabilitation interventions were designed and performed focusing on neurodevelopmental delay. Because she had a severe developmental delay and her scores in all five domains of ASQ-2 were below the cut-off points available for Iranian children, the effectiveness of rehabilitation interventions was slower than expected. It seems that early rehabilitation and close follow-up should be considered for these children. We can assume that early and properly sensory-motor and cognitive interventions in these children may lead to growth development and prevent secondary complications.

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A novel de novo KDM5C variant in a female with global developmental delay and ataxia: a case report

BMC Neurology ◽

10.1186/s12883-021-02380-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Natalie C. Lippa ◽

Subit Barua ◽

Vimla Aggarwal ◽

Elaine Pereira ◽

Jennifer M. Bain

Keyword(s):

Case Report ◽

Intellectual Disability ◽

Short Stature ◽

Developmental Delay ◽

De Novo ◽

Phenotypic Variability ◽

Missense Variant ◽

Global Developmental Delay ◽

Related Disorder ◽

Patient Reported

Abstract Background Pathogenic variants in KDM5C are a cause of X-linked intellectual disability in males. Other features in males include short stature, dysmorphic features, seizures and spasticity. In some instances, female relatives were noted to have learning difficulties and mild intellectual disabilities, but full phenotypic descriptions were often incomplete. Recently, detailed phenotypic features of five affected females with de novo variants were described. (Clin Genet 98:43–55, 2020) Four individuals had a protein truncating variant and 1 individual had a missense variant. All five individuals had developmental delay/intellectual disability and three neurological features. Case presentation Here we report a three-year-old female with global developmental delay, hypotonia and ataxia. Through whole exome sequencing, a de novo c.1516A > G (p.Met506Val) variant in KDM5C was identified. This missense variant is in the jumonji-C domain of this multi domain protein where other missense variants have been previously reported in KDM5C related disorder. The KDM5C gene is highly intolerant to functional variation which suggests its pathogenicity. The probands motor delays and language impairment is consistent with other reported female patients with de novo variants in KDM5C. However, other features reported in females (distinctive facial features, skeletal abnormalities, short stature and endocrine features) were absent. To the best of our knowledge, our proband is the first female patient reported with a diagnosis of ataxia. Conclusions This case report provides evidence for an emerging and phenotypic variability that adds to the literature of the role of KDM5C in females with neurodevelopmental disorders as well as movement disorders.

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

Oxford Medical Case Reports ◽

10.1093/omcr/omab079 ◽

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.

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