A homozygous missense variant in the MLC1 gene underlies megalencephalic leukoencephalopathy with subcortical cysts in large kindred: Heterozygous carriers show seizure and mild motor function deterioration

A population-specific missense variant rs1597000001 in CETP promotes a favorable lipid profile and reduces CETP activity

10.1101/2021.09.11.21263438 ◽

2021 ◽

Author(s):

Jaye Moors ◽

Mohanraj Krishnan ◽

Nick Sumpter ◽

Riku Takei ◽

Matt Bixley ◽

...

Keyword(s):

Lipid Profile ◽

Missense Variant ◽

Study Cohort ◽

Loss Of Function ◽

Lower Plasma ◽

Heterozygous Carriers

ABSTRACTSequencing of CETP in Māori and Pacific peoples identified a common (MAF ∼2.4%-5.4%) population-specific missense variant (rs1597000001, CETP:c.530C>T p.Pro177Leu) that associates with higher HDL-C levels ( [95% CI 0.211; 0.260]) and lower LDL-C ( [95% CI -0.209; -0.058]). In a subsample of the study cohort (n = 11), heterozygous carriers of the population-specific variant had lower plasma CETP activity (P = 0.028). Our study identifies a population-specific missense variant in CETP which lowers CETP activity with an effect on HDL-C that is comparable to Mendelian CETP loss-of-function mutations.

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A spectrum of recessiveness among Mendelian disease variants in UK Biobank

10.1101/2021.12.13.21267756 ◽

2021 ◽

Author(s):

Alison R Barton ◽

Margaux L.A. Hujoel ◽

Ronen E. Mukamel ◽

Maxwell A Sherman ◽

Po-Ru Loh

Keyword(s):

Cystic Fibrosis ◽

Allelic Variation ◽

Muscular Atrophy ◽

Missense Variant ◽

Incomplete Penetrance ◽

Mendelian Disease ◽

Uk Biobank ◽

Association Analyses ◽

Increased Risk ◽

Heterozygous Carriers

Recent work has found increasing evidence of mitigated, incompletely penetrant phenotypes in heterozygous carriers of recessive Mendelian disease variants. We leveraged whole-exome imputation within the full UK Biobank cohort (N~500K) to extend such analyses to 3,481 rare variants curated from ClinVar and OMIM. Testing these variants for association with 57 quantitative traits yielded 103 significant associations involving variants previously implicated in 35 different diseases. Notable examples included a POR missense variant implicated in Antley-Bixler syndrome that associated with a 1.76 (s.e. 0.27) cm increase in height, and an ABCA3 missense variant implicated in interstitial lung disease that associated with reduced FEV1/FVC ratio. Association analyses with 1,257 disease traits yielded five additional variant-disease associations. We also observed contrasting levels of recessiveness between two more-common, classical Mendelian diseases. Carriers of cystic fibrosis variants exhibited increased risk of several mitigated disease phenotypes, whereas carriers of spinal muscular atrophy alleles showed no evidence of altered phenotypes. Incomplete penetrance of cystic fibrosis carrier phenotypes did not appear to be mediated by common allelic variation on the functional haplotype. Our results show that many disease-associated recessive variants can produce mitigated phenotypes in heterozygous carriers and motivate further work exploring penetrance mechanisms.

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Variant Analysis of Alkaptonuria Families with Significant Founder Effect in Jordan

BioMed Research International ◽

10.1155/2021/1515641 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Raida Khalil ◽

Dema Ali ◽

Nesrin Mwafi ◽

Arwa Alsaraireh ◽

Loiy Obeidat ◽

...

Keyword(s):

Autosomal Recessive ◽

Family Members ◽

Autosomal Recessive Disorder ◽

Missense Variant ◽

Homogentisic Acid ◽

Common Variants ◽

Genetic Features ◽

Heterozygous Carriers ◽

Variant Analysis ◽

Age Range

Background. Metabolic disorder alkaptonuria is an autosomal recessive disorder caused by mutations in the HGD gene, and a deficiency HGD enzyme activity results in an accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue. Methods. We clinically evaluated 18 alkaptonuria patients (age range, 3 to 60 years) from four unrelated families. Furthermore, 11 out of 18 alkaptonuria patients and 7 unaffected members were enrolled for molecular investigations by utilizing Sanger sequencing to identify variants of the 14 exons of HGD gene. Results. We found that the seven patients from the 4 unrelated families carried a recurrent pathogenic missense variant (c.365C>T, p. Ala122Val) in exon 6 of HGD gene. The variant was fully segregated with the disease in affected family members while the other unaffected family members were heterozygous carriers for this variant. Additionally, the clinical features were fully predicted with alkaptonuria disorder. Conclusion. In this study, we confirmed that the most common variants in Jordanian AKU patients was c.365C>T, p. Ala122Val in exon 6 of HGD gene. Additionally, we correlated the clinical and genetic features of AKU patients at various ages (3-60 years).

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Prevalence of Speech Problems and the Use of Augmentative and Alternative Communication in Children With Cerebral Palsy: A Registry-Based Study in Norway

Perspectives on Augmentative and Alternative Communication ◽

10.1044/aac19.1.12 ◽

2010 ◽

Vol 19 (1) ◽

pp. 12-20 ◽

Cited By ~ 29

Author(s):

Guro Andersen ◽

Tone R. Mjøen ◽

Torstein Vik

Keyword(s):

Cerebral Palsy ◽

Motor Function ◽

Gestational Age ◽

Augmentative And Alternative Communication ◽

Alternative Communication ◽

Gross Motor ◽

Gross Motor Function ◽

Children With Cerebral Palsy ◽

Communicative Abilities ◽

Normal Speech

Abstract This study describes the prevalence of speech problems and the use of augmentative and alternative communication (AAC) in children with cerebral palsy (CP) in Norway. Information on the communicative abilities of 564 children with CP born 1996–2003, recorded in the Norwegian CP Registry, was collected. A total of 270 children (48%) had normal speech, 90 (16%) had slightly indistinct speech, 52 (9%) had indistinct speech, 35 (6%) had very indistinct speech, 110 children (19%) had no speech, and 7 (1%) were unknown. Speech problems were most common in children with dyskinetic CP (92 %), in children with the most severe gross motor function impairments and among children being totally dependent on assistance in feeding or tube-fed children. A higher proportion of children born at term had speech problems when compared with children born before 32 weeks of gestational age 32 (p > 0.001). Among the 197 children with speech problems only, 106 (54%) used AAC in some form. Approximately 20% of children had no verbal speech, whereas ~15% had significant speech problems. Among children with either significant speech problems or no speech, only 54% used AAC in any form.

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