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At least 19 recordsLinked to original sources
PubMed1976

[Genetic analysis of microcephaly].

A clinical genetic examination of 22 cases of hereditary microcephaly in 11 families was carried out. Parent consanguinity (first and second cousins) was ascertained in 7 families. Genetic analysis of the experimental material performed by Weinberg's method showed significantly recessive course of the genuine microcephaly inheritance. High frequency of low degree mental retardation (30%) among probable recessive genes carriers of microcephaly (of the parents and their siblings) was ascertained and that confirmed the possibility of gene heterozygous state manifestation. The gene frequency fluctuated from 0,0042 to 0,024. About 3500 people might show low forms of mental retardation in connection with probable non-penetration (about 30%) of the microcephaly genes being in heterozygols state.

Consanguinity↗
PubMed2024

Dual diagnosis of achondroplasia and mandibulofacial dysostosis with microcephaly.

BACKGROUND: Achondroplasia and mandibulofacial dysostosis with microcephaly (MFDM) are rare monogenic, dominant disorders, caused by gain-of-function fibroblast growth factor receptor 3 (FGFR3) gene variants and loss-of-function elongation factor Tu GTP binding domain-containing 2 (EFTUD2) gene variants, respectively. The coexistence of two distinct Mendelian disorders in a single individual is uncommon and challenges the traditional paradigm of a single genetic disorder explaining a patient's symptoms, opening new avenues for diagnosis and management. CASE PRESENTATION: We present a case of a female patient initially diagnosed with achondroplasia due to a maternally inherited pathogenic FGFR3 variant. She was referred to our genetic department due to her unusually small head circumference and short stature, which were both significantly below the expected range for achondroplasia. Additional features included distinctive facial characteristics, significant speech delay, conductive hearing loss, and epilepsy. Given the complexity of her phenotype, she was recruited to the DDD (Deciphering Developmental Disorders) study and the 100,000 Genomes project for further investigation. Subsequent identification of a complex EFTUD2 intragenic rearrangement confirmed an additional diagnosis of mandibulofacial dysostosis with microcephaly (MFDM). CONCLUSION: This report presents the first case of a dual molecular diagnosis of achondroplasia and mandibulofacial dysostosis with microcephaly in the same patient. This case underscores the complexity of genetic diagnoses and the potential for coexistence of multiple genetic syndromes in a single patient. This case expands our understanding of the molecular basis of dual Mendelian disorders and highlights the importance of considering the possibility of dual molecular diagnoses in patients with phenotypic features that are not fully accounted for by their primary diagnosis.

Humans↗
PubMed1979

Autosomal dominant microcephaly.

Four families with autosomal dominant microcephaly are reported. Although the phenotype is nondistinctive, several patients had receding or small foreheads, upslanted palpebral fissures, or prominent ears. The degree of intellectual dysfunction is not as severe as that recorded in autosomal recessive microcephaly. It would appear that autosomal dominant microcephaly is more common than previously recorded, and that head circumference measurements of siblings and parents of affected patients should become a part of the initial investigation.

Adult↗
PubMed2025

Loss-of-Function CARS1 Variants in a Patient With Microcephaly, Developmental Delay, and a Brittle Hair Phenotype.

BACKGROUND: Mutations in cysteinyl-tRNA synthetase (CARS1) have been implicated in a multisystem disease including microcephaly, developmental delay, and brittle hair and nail phenotypes. METHODS: Here, we present a patient with hepatopathy, hypothyroidism, short stature, developmental delay, microcephaly, muscular hypotonia, brittle hair, and ataxia. The patient underwent exome sequencing to identify potentially pathogenic genetic variants. In addition, identified variants were assessed using yeast complementation assays to determine functional consequences. RESULTS: Exome sequencing determined that the patient is compound heterozygous for p.Arg341His and p.Arg370Trp CARS1. Yeast complementation assays showed that the p.Arg341His variant has a hypomorphic effect and that the p.Arg370Trp variant causes a complete loss-of-function effect. CONCLUSION: This study is the second report of pathogenic CARS1 variants and expands the allelic and phenotypic heterogeneity of CARS1-associated disease.

Humans↗
PubMed2024

Loss-of-function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly.

PURPOSE: Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 and has not been implicated in human disease. METHODS: We identify 5 unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and 2 missense variants were identified in probands with neurodevelopmental symptoms, including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models. RESULTS: Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the interface between RBBP5 and the nucleosome. In Drosophila, overexpression analysis identifies partial loss-of-function mechanisms when the variants are expressed using the fly Rbbp5 or human RBBP5 cDNA. Loss of Rbbp5 leads to a reduction in brain size. The human reference or variant transgenes fail to rescue this loss and expression of either missense variant in an Rbbp5 null background results in a less severe microcephaly phenotype than the human reference, indicating both missense variants are partial loss-of-function alleles. CONCLUSION: Haploinsufficiency of RBBP5 observed through de novo null and hypomorphic loss-of-function variants is associated with a syndromic neurodevelopmental disorder.

Humans↗
PubMed1979

The Bowen-Conradi syndrome -- a highly lethal autosomal recessive syndrome of microcephaly, micrognathia, low birth weight, and joint deformities.

This paper describes six Hutterite children from five families who appear to have been affected by the same syndrome that was described in two brothers by Bowen and Conradi [1]. Our additional cases confirm that the major features of the syndrome include porportionate intrauterine growth retardation, microcephaly, micrognathia, a prominent nose, rocker-bottom feet, joint limitation, and failure to thrive, with death within the first year of life. Bowen-Conradi syndrome is an autosomal recessive trait and pedigree records show that all six families now known are related to each other through two couples born in the late 1700s but that there are additional earlier possible sources of the responsible gene. The differential diagnosis of this syndrome is discussed.

Abnormalities, Multiple↗
PubMed1979

Pre and post axial polysyndactyly, microcephaly and ptosis.

A five-year-old boy of Iranian origin with multiple anomalies is described. His parents are first and second cousins. He presented with short stature, psychomotor retardation, microcephaly, ptosis, dacryostenosis, partial left nerve deafness, high arched palate, bifid uvula, total fusion between incisors, asymmetric preaxial and postaxial polysyndactyly, brachyphalangy, kyphosis and spina bifida occulta of S1. To our knowledge, a similar case has not been reported previously.

Abnormalities, Multiple↗
PubMed1977

Microcephaly with peculiar demyelination mimicking Pelizaeus-Merzbacher disease.

The neuropathological studies of a 4-year old idiot with microcephaly revealed a striking demyelinating disease compatible with Pelizaeus-Merzbacher disease. The case seemed to be best classified as the patchy demyelination type, but the most unusual finding was a prominent vasculature in some demyelinated areas. Intrauterine hypoxia was proposed as a causative factor of this type of demyelinative lesions.

Autopsy↗
PubMed2025

Insights into KIF11 pathogenesis in microcephaly-lymphedema-chorioretinopathy syndrome from a lymphatic perspective.

Pathogenic variants in kinesin KIF11 underlie microcephaly-lymphedema-chorioretinopathy (MLC) syndrome. Although well known for regulating spindle dynamics ensuring successful cell division, the association of KIF11 (encoding EG5) with development of the lymphatic system and how KIF11 pathogenic variants lead to lymphatic dysfunction and lymphedema remain unknown. Using patient-derived lymphoblastoid cells, we demonstrated that patients with MLC carrying pathogenic stop-gain variants in KIF11 have reduced mRNA and protein levels. Lymphoscintigraphy showed reduced tracer absorption, and intestinal lymphangiectasia was detected in one patient, pointing to impairment of lymphatic function caused by KIF11 haploinsufficiency. We revealed that KIF11 is expressed in early human and mouse development with the lymphatic markers VEGFR3, podoplanin, and PROX1. In zebrafish, single-cell RNA-Seq identified kif11 specifically expressed in endothelial precursors. In human lymphatic endothelial cells, EG5 inhibition with ispinesib reduced VEGFC-driven AKT phosphorylation, migration, and spheroid sprouting. KIF11 knockdown reduced PROX1 and VEGFR3 expression, providing for the first time to our knowledge a link between KIF11 and drivers of lymphangiogenesis and lymphatic identity.

Humans↗
PubMed2026

RETRACTION: Loss-of-Function CARS1 Variants in a Patient With Microcephaly, Developmental Delay, and a Brittle Hair Phenotype.

C. Del Greco, M. E. Kuo, D. E. C. Smith, M. I. Mendes, G. S. Salamons, M. Nemcovic, R. Kodrikova, S. Sestak, M. Stancheva, and A. Antonellis, "Loss-of-Function CARS1 Variants in a Patient With Microcephaly, Developmental Delay, and a Brittle Hair Phenotype," Molecular Genetics & Genomic Medicine 13, no. 2 (2025): e70078, https://doi.org/10.1002/mgg3.70078. The above article, published online on 18 February 2025 in Wiley Online Library (https://onlinelibrary.wiley.com/), has been retracted by agreement between the authors; the journal Editor-in-Chief, Paraminder Dhillon; and Wiley Periodicals, LLC. The retraction has been agreed upon due to the lack of appropriate authorization for the publication of the CARS1 variants related to the specific patient described in this clinical report. In addition, written consent for publication was not obtained from the child's legal guardian.

Journal Article↗
PubMed1976

Microcephaly.

Explore the source record for details and available documents.

Child, Preschool↗
PubMed1978

Newborn head size and neurological status. Predictors of growth and development of low birth weight infants.

One hundred eighteen infants with birth weights of 2,000 g or less were evaluated for growth and development at approximately 5 years of age. Review of neonatal data indicated that head circumference less than the tenth percentile at birth and abnormal neurological examination in the newborn period were important predictors of outcome. Both of these factors were associated with poor growth, later microcephaly, and neurological deficit. In addition, neonatal microcephaly was substantially related to poor intellectual attainment. Other associations were seen between microcephaly at birth and intrauterine growth retardation, low Apgar score, and low socioeconomic status, factors that also correlated with poor outcome.

Apgar Score↗
PubMed2024

Cilia defects upon loss of WDR4 are linked to proteasomal hyperactivity and ubiquitin shortage.

The WD repeat-containing protein 4 (WDR4) has repeatedly been associated with primary microcephaly, a condition of impaired brain and skull growth. Often, faulty centrosomes cause microcephaly, yet aberrant cilia may also be involved. Here, we show using a combination of approaches in human fibroblasts, zebrafish embryos and patient-derived cells that WDR4 facilitates cilium formation. Molecularly, we associated WDR4 loss-of-function with increased protein synthesis and concomitant upregulation of proteasomal activity, while ubiquitin precursor pools are reduced. Inhibition of proteasomal activity as well as supplementation with free ubiquitin restored normal ciliogenesis. Proteasome inhibition ameliorated microcephaly phenotypes. Thus, we propose that WDR4 loss-of-function impairs head growth and neurogenesis via aberrant cilia formation, initially caused by disturbed protein and ubiquitin homeostasis.

Animals↗
PubMed2023

H4C5 missense variant leads to a neurodevelopmental phenotype overlapping with Angelman syndrome.

Recurrent de novo missense variants in H4 histone genes have recently been associated with a novel neurodevelopmental syndrome that is characterized by intellectual disability and developmental delay as well as more variable findings that include short stature, microcephaly, and facial dysmorphisms. A 4-year-old male with autism, developmental delay, microcephaly, and a happy demeanor underwent evaluation through the Undiagnosed Disease Network. He was clinically suspected to have Angelman syndrome; however, molecular testing was negative. Genome sequencing identified the H4 histone gene variant H4C5 NM_003545.4: c.295T>C, p.Tyr99His, which parental testing confirmed to be de novo. The variant met criteria for a likely pathogenic classification and is one of the seven known disease-causing missense variants in H4C5. A comparison of our proband's findings to the initial description of the H4-associated neurodevelopmental syndrome demonstrates that his phenotype closely matches the spectrum of those reported among the 29 affected individuals. As such, this report corroborates the delineation of neurodevelopmental syndrome caused by de novo missense H4 gene variants. Moreover, it suggests that cases of clinically suspected Angelman syndrome without molecular confirmation should undergo exome or genome sequencing, as novel neurodevelopmental syndromes with phenotypes overlapping with Angelman continue to be discovered.

Male↗