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Mendeliome v1.4153 PLXNA1 Lucy Spencer changed review comment from: All 3 de novo missense variants in Dworschak et al. (2021) are present in gnomad v4 with 21, 2 and 4 heterozygotes. There is an additional de novo patient in Park 2017 PMID: 28464511, however their variant is also present in gnomad v4 with 5 heterozygotes. There is no recent literature supporting the dominant association

The monoallelic assertion for this gene is now RED, still GREEN for biallelic; to: All 3 de novo missense variants in Dworschak et al. (2021) are present in gnomad v4 with 21, 2 and 4 heterozygotes. There is an additional de novo patient in Park 2017 PMID: 28464511, however their variant is also present in gnomad v4 with 5 heterozygotes. There is no recent literature supporting the dominant association

The monoallelic assertion for a neurodevelopmental disorder in this gene is now RED, still GREEN for biallelic
Mendeliome v1.4153 PLXNA1 Lucy Spencer edited their review of gene: PLXNA1: Changed publications: 34054129, 28464511, 28334861, 30467832, 34636164; Changed phenotypes: Dworschak-Punetha neurodevelopmental syndrome, MIM# 619955, Hypogonadotropic hypogonadism MONDO:0018555, PLXNA1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.4153 PLXNA1 Lucy Spencer Publications for gene: PLXNA1 were set to 34054129; 28464511
Mendeliome v1.4152 PLXNA1 Lucy Spencer Phenotypes for gene: PLXNA1 were changed from Dworschak-Punetha neurodevelopmental syndrome, MIM# 619955 to Dworschak-Punetha neurodevelopmental syndrome, MIM# 619955; Hypogonadotropic hypogonadism MONDO:0018555, PLXNA1-related
Mendeliome v1.4151 PLXNA1 Lucy Spencer Mode of inheritance for gene: PLXNA1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.4150 PLXNA1 Lucy Spencer edited their review of gene: PLXNA1: Added comment: reported phenotype expansion for monoallelic Kallman syndrome:
PMIDs 28334861 13 families with Kallman syndrome, however only 3 of these variants (His684Tyr Lys1618Thr Cys1744Phe) are absent from gnomad, the rest have at least 6 hets and most have over 20 hets. in transfected cells His684Tyr, Lys1618Thr and some of the common missense variants were shown to result in reduced total amounts of protein. In a minigene assay Cys1744Phe which is at the last base of an exon was shown to cause intron 28 retention which would be out of frame. No variants in this study were noted to be de novo.

PMID: 30467832 10 missense variants identified in patients with hypogonadotropic hypogonadism. Again some of the reported missense have over 20 hets in gnomad but 5 of the variants are rare or absent Lys1451Arg, Ser1850Arg, Ile1701Val, Pro485Leu and Val536Ile. All of these variants were either inherited from a parent or inheritance was unknown, and 1 individual had a better diagnosis with a nonsense in FGFR1 while other patients had variants in other genes amber for HH. No variants in this study were noted to be de novo.

PMID: 34636164 another 10 missense variants identified in 11 families with hypogonadotropic hypogonadism. However, only 3 were not common in gnomad; Pro848Arg, Ala1106Val, and Ser1709Leu. Ala1106Val and Ser1709Leu were both inherited from unaffected mothers, and most patients in this study also had variants of interest in other genes. No variants in this study were noted to be de novo.

So at least 10 reports of variants that are rare/absent in gnomad with Kallman syndrome, all missense variants, most without segregation information or inherited from unaffected/unknown if affected parents. Some with a bit of functional work. Many patients also have variants of interest in other genes amber or green for the same phenotype. borderline amber/green; Changed rating: AMBER; Changed phenotypes: Hypogonadotropic hypogonadism MONDO:0018555, PLXNA1-related
Mendeliome v1.3773 PLXNA1 Lucy Spencer Publications for gene: PLXNA1 were set to 34054129
Mendeliome v1.3772 PLXNA1 Lucy Spencer changed review comment from: All 3 de novo missense variants in Dworschak et al. (2021) are present in gnomad v4 with 21, 2 and 4 heterozygotes. There is an additional de novo patient in Park 2017 PMID: 28464511, however their variant is also present in gnomad v4 with 5 heterozygotes. There is no new literature supporting the dominant association

The monoallelic assertion for this gene is now RED, still GREEN for biallelic; to: All 3 de novo missense variants in Dworschak et al. (2021) are present in gnomad v4 with 21, 2 and 4 heterozygotes. There is an additional de novo patient in Park 2017 PMID: 28464511, however their variant is also present in gnomad v4 with 5 heterozygotes. There is no recent literature supporting the dominant association

The monoallelic assertion for this gene is now RED, still GREEN for biallelic
Mendeliome v1.3772 PLXNA1 Lucy Spencer edited their review of gene: PLXNA1: Changed rating: RED; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.3772 PLXNA1 Lucy Spencer changed review comment from: All 3 de novo missense variants in Dworschak et al. (2021) are present in gnomad v4 with 21, 2 and 4 heterozygotes. There is an additional de novo patient in Park 2017 PMID: 28464511, however their variant is also present in gnomad v4 with 5 heterozygotes. There is no new literature supporting the dominant association

The monoallelic assertion for this gene is now RED, still GREEN for biallelic; to: All 3 de novo missense variants in Dworschak et al. (2021) are present in gnomad v4 with 21, 2 and 4 heterozygotes. There is an additional de novo patient in Park 2017 PMID: 28464511, however their variant is also present in gnomad v4 with 5 heterozygotes. There is no new literature supporting the dominant association

The monoallelic assertion for this gene is now RED, still GREEN for biallelic
Mendeliome v1.3772 PLXNA1 Lucy Spencer Mode of inheritance for gene: PLXNA1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.3771 PLXNA1 Lucy Spencer commented on gene: PLXNA1
Mendeliome v1.152 PLXNA1 Zornitza Stark Phenotypes for gene: PLXNA1 were changed from Neurodevelopmental disorder with cerebral and eye anomalies to Dworschak-Punetha neurodevelopmental syndrome, MIM# 619955
Mendeliome v1.151 PLXNA1 Zornitza Stark edited their review of gene: PLXNA1: Changed phenotypes: Dworschak-Punetha neurodevelopmental syndrome, MIM# 619955
Mendeliome v0.9334 PLXNA1 Zornitza Stark Marked gene: PLXNA1 as ready
Mendeliome v0.9334 PLXNA1 Zornitza Stark Gene: plxna1 has been classified as Green List (High Evidence).
Mendeliome v0.9334 PLXNA1 Zornitza Stark Classified gene: PLXNA1 as Green List (high evidence)
Mendeliome v0.9334 PLXNA1 Zornitza Stark Gene: plxna1 has been classified as Green List (High Evidence).
Mendeliome v0.9333 PLXNA1 Zornitza Stark gene: PLXNA1 was added
gene: PLXNA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLXNA1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PLXNA1 were set to 34054129
Phenotypes for gene: PLXNA1 were set to Neurodevelopmental disorder with cerebral and eye anomalies
Review for gene: PLXNA1 was set to GREEN
Added comment: Dworschak et al. (2021) via WES reported 10 patients from 7 families with biallelic (n=7) or de novo (n=3) PLXNA1 variants. Shared phenotypic features include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Seizures were predominantly reported in patients with monoallelic variants. Zebrafish studies showed an embryonic role of plxna1a in the development of the central nervous system and the eye. Biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.
Sources: Literature