Prenatal diagnosis of microcephaly as shown by plateauing of head circumference growth during the 3rd trimester in a fetus with a CCND2 inverse growth variant

Malinger, G.; Haratz, Karina Krajden; Birnbaum, R.; Tsur, Erez; Berger, R; Shohat, Mordechai

doi:10.1002/pd.6148

Cited by 3 publications

(2 citation statements)

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“…4 D). Putative CCND2 loss of function variants have been previously reported as a strong microcephaly candidate gene in four unrelated patients [ 16 , 17 ]. The variant p.Gln169Ter was likely to be disease causing as a loss of function effect because (1) the variant is predicted to cause loss of function, because the resulting mRNA transcript is likely to subjected nonsense-mediated decay (Fig.…”

Section: Resultsmentioning

confidence: 99%

Diagnostic yield and novel candidate genes for neurodevelopmental disorders by exome sequencing in an unselected cohort with microcephaly

et al. 2023

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Objectives Microcephaly is caused by reduced brain volume and most usually associated with a variety of neurodevelopmental disorders (NDDs). To provide an overview of the diagnostic yield of whole exome sequencing (WES) and promote novel candidates in genetically unsolved families, we studied the clinical and genetic landscape of an unselected Chinese cohort of patients with microcephaly. Methods We performed WES in an unselected cohort of 103 NDDs patients with microcephaly as one of the features. Full evaluation of potential novel candidate genes was applied in genetically undiagnosed families. Functional validations of selected variants were conducted in cultured cells. To augment the discovery of novel candidates, we queried our genomic sequencing data repository for additional likely disease-causing variants in the identified candidate genes. Results In 65 families (63.1%), causative sequence variants (SVs) and clinically relevant copy number variants (CNVs) with a pathogenic or likely pathogenic (P/LP) level were identified. By incorporating coverage analysis to WES, a pathogenic or likely pathogenic CNV was detected in 15 families (16/103, 15.5%). In another eight families (8/103, 7.8%), we identified variants in newly reported gene (CCND2) and potential novel neurodevelopmental disorders /microcephaly candidate genes, which involved in cell cycle and division (PWP2, CCND2), CDC42/RAC signaling related actin cytoskeletal organization (DOCK9, RHOF), neurogenesis (ELAVL3, PPP1R9B, KCNH3) and transcription regulation (IRF2BP1). By looking into our data repository of 5066 families with NDDs, we identified additional two cases with variants in DOCK9 and PPP1R9B, respectively. Conclusion Our results expand the morbid genome of monogenic neurodevelopmental disorders and support the adoption of WES as a first-tier test for individuals with microcephaly.

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Section: Resultsmentioning

confidence: 99%

Diagnostic yield and novel candidate genes for neurodevelopmental disorders by exome sequencing in an unselected cohort with microcephaly

et al. 2023

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“…Advances in genetic testing can reduce the false negative rate. Malinger et al (2022) reported a case in which deceleration of HC growth rate was shown starting at 23 weeks of gestation, and at 37 weeks the HC was 2.4 SD below the mean for gestational age. The initial work-up was negative, MRI showed nonspecific brain findings, but the WES trio results revealed a heterozygous de-novo splicing (loss of function) variant in CCND2 gene.…”

Section: False Negative Diagnosis Of Fetal Microcephalymentioning

confidence: 99%

Small size, big problems: insights and difficulties in prenatal diagnosis of fetal microcephaly

Haddad,

Hadi,

Leibovitz

et al. 2024

Front. Neurosci.

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Microcephaly is a sign, not a diagnosis. Its incidence varies widely due to the differences in the definition and the population being studied. It is strongly related to neurodevelopmental disorders. Differences in definitions and measurement techniques between fetuses and newborns pose a great challenge for the diagnosis and prognostication of fetal microcephaly. A false positive diagnosis can result (in countries where it is legal) in erroneous termination of pregnancy, where a false negative diagnosis might lead to the birth of a microcephalic newborn. Microcephaly in growth restricted fetuses deserves special attention and separate evaluation as it is an important prognostic factor, and not necessarily part of the general growth retardation. Several genetic syndromes incorporating microcephaly and intrauterine growth retardation (IUGR) are discussed. Deceleration of the head circumference (HC) growth rate even when the HC is still within normal limits might be the only clue for developing microcephaly and should be considered during fetal head growth follow up. Combining additional parameters such as a positive family history, associated anomalies, and new measurement parameters can improve prediction in about 50% of cases, and thus should be part of the prenatal workup. Advances in imaging modalities and in prenatal genetic investigation along with the emergence of new growth charts can also improve diagnostic accuracy. In this article, we review the different definitions and etiologies of fetal microcephaly, discuss difficulties in diagnosis, investigate the reasons for the low yield of prenatal diagnosis, and provide improvement suggestions. Finally, we suggest an updated algorithm that will aid in the diagnosis and management of fetal microcephaly.

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