Mendeliome
Gene: PLXNA1 Green List (high evidence)I don't know
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/greenCreated: 23 Jan 2026, 4:02 p.m. | Last Modified: 23 Jan 2026, 4:02 p.m.
Panel Version: 1.4150
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 biallelicCreated: 12 Dec 2025, 10:52 a.m. | Last Modified: 23 Jan 2026, 4:09 p.m.
Panel Version: 1.4153
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Dworschak-Punetha neurodevelopmental syndrome, MIM# 619955; Hypogonadotropic hypogonadism MONDO:0018555, PLXNA1-related
Publications
Green List (high evidence)
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: LiteratureCreated: 7 Oct 2021, 12:05 p.m.
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Dworschak-Punetha neurodevelopmental syndrome, MIM# 619955
Publications
Publications for gene: PLXNA1 were set to 34054129; 28464511
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
Mode of inheritance for gene: PLXNA1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PLXNA1 were set to 34054129
Mode of inheritance for gene: PLXNA1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PLXNA1 were changed from Neurodevelopmental disorder with cerebral and eye anomalies to Dworschak-Punetha neurodevelopmental syndrome, MIM# 619955
Gene: plxna1 has been classified as Green List (High Evidence).
Gene: plxna1 has been classified as Green List (High Evidence).
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
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.