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Growth and Neurodevelopmental Disorder with Arthrogryposis, Microcephaly and Structural Brain Anomalies Caused by Biallelic Partial Deletion of SMPD4 gene https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8930277/

nihms-1741821.pdf

We report a 22-month-old girl having characteristic features of neurodevelopmental delay, prenatal onset growth failure, arthrogryposis, microcephaly and brain anomalies including severe hypomyelination, simplified gyral pattern and hypoplasia of corpus callosum and brainstem

Individuals with homozygous missense variants had milder phenotype compared to individuals with truncating variants in SMPD4 [3]

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Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis https://www.cell.com/ajhg/fulltext/S0002-9297(19)30309-X

mmc5.pdf

• 12 unrelated families, 32 individuals w 21 w detailed clinical info
• Phenotype: microcephaly, simplified gyration, hypomyelination, thin corpus callosum, mild cerebellar hypoplasia, brainstem hypoplasia, congenital arthrogryposis, diabetes mellitus, heart disease, severe encephalopathy respiratory problems often leading to early demise.

Clinical Features Progressive microcephalyb 9/10 90% Seizures 10/17 58.8% Persistent respiratory distressc 11/18 61.1% Congenital arthrogryposis 17/20 85% Developmental delay 7/7 100% Facial dysmorphisms 15/15 100% Congenital heart defect 12/21 57.1% Diabetes mellitus 2/19 10.5% Muscular tone Hypotonic 4/15 26.7% Hypertonic 9/15 60% Normotonic 2/15 13.3%

Three missense changes were identified, all predicted to have damaging but unexplored effects on SMPD4 protein, that could have altered function, structure, or stability. The homozygous p.Pro344Leu variant was found in the longest surviving children of family 9, who developed motor skills such as independent walking, unlike individuals with biallelic truncating variants, suggesting the persistence of residual SMPD4 function. Any clinical benefits of a possible residual function associated to the second missense change (p.Leu231Pro) in family 7 are probably hampered by the complete absence of the other allele, due to a contiguous gene deletion involving the entire SMPD4 sequence. At the (neurological) mildest end of the spectrum, the twins of family 11 have microcephaly, arthrogryposis, and pectus excavatum, stature within the normal range, an important congenital heart disease, and only a mild intellectual disability. Their MRI scans do not show simplified gyration, one of them showing signs of perinatal asphyxia with cortical infarcts. Notably, the c.3878G>A variant in these subjects has a lower CADD score, indicating the relative milder splice anomaly, hence the possibility of higher percentage of normal transcript

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Case Report: Novel Biallelic Null Variants of SMPD4 Confirm Its Involvement in Neurodevelopmental Disorder With Microcephaly, Arthrogryposis, and Structural Brain Anomalies https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9149365/

fgene-13-872264 (1).pdf

Individuals with biallelic null mutations always exhibit more severe phenotypes, such as brain structural abnormalities, arthrogryposis, and early death

Although only 28 individuals with NEDMABA have been reported, this may be an underestimate; the prevalence estimated based on the gene carrier rate (Guo and Gregg, 2019) calculated from loss-of-function variants of SMPD4 in gnomAD is about one in 1,580,000

This may be attributable to the fact that the typical symptoms of NEDMABA are nonspecific, making clinical diagnosis difficult.

Notably, this individual shared the same homozygous null variant with another case of Arab descent (Family 5) who presented typical symptoms. Thus, skeletal dysplasia and brain atrophy are not variant-specific features.

Interesting comment ^ on excluding features

Individuals with biallelic null mutations always exhibit more severe phenotypes

How do we measure this ^

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NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, ARTHROGRYPOSIS, AND STRUCTURAL BRAIN ANOMALIES; NEDMABA https://omim.org/entry/618622

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Neurogenetic fetal akinesia and arthrogryposis: genetics, expanding genotype-phenotypes and functional genomics.

nihms-1720922.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328565/

Fetal akinesia or hypokinesia can result in a range of clinical presentations, including; fetal akinesia deformation sequence (FADS),1 arthrogryposis multiplex congenita (AMC), distal arthrogryposis (DA),2 lethal congenital contracture syndromes (LCCS), and multiple pterygium syndrome (MPS). Many of these conditions have overlapping features including: joint contractures, pterygia, fetal hydrops, lung hypoplasia and dysmorphic features.

The clinical and genetic heterogeneity, along with the sporadic nature of the disease or small families, meant that genetic testing was difficult or unattainable beyond a handful of known genes or gene hotspots

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Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562004/

main (5).pdf

The limited sensitivity of clinical evaluation even by genetic experts probably reflects the established challenge of the extreme heterogeneity of Mendelian disorders