Description
Paediatric motor neuronopathies eligibility statement:

Relevant diseases:

- Brown-Vialetto-Van Laere syndrome
- Spinal muscular atrophy with respiratory distress
- Fazio-Londe syndrome

Paediatric motor neuronopathies inclusion criteria (29519)
- Bulbar palsy +/- sensorineural deafness, visual impairment, seizures, motor and/or global developmental delay
- Congenital or presentation in early childhood most commonly (presentation can occur in adult life, but is rare)
- Full neurometabolic screen completed with normal/inconclusive findings
- EMG consistent with bulbar palsy +/- evidence of more extensive motor neuron involvement

Paediatric motor neuronopathies exclusion criteria (29519)

Prior genetic testing guidance (29519)
- Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. 
- Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.  

PLEASE NOTE: The sensitivity of WGS compared to current diagnostic genetic testing has not yet been established. It is therefore important that tests which are clinically indicated under local standard practice continue to be carried out.

Closing statement (29519)
These requirements will be kept under continual review during the main programme and may be subject to change.

5 reviewers

  • Ellen McDonagh (Genomics England Curator)

    Group: other
    Workplace: other

  • Alice Gardham (Genomics England)

    Group: Other
    Workplace: Other

  • Dragana Josifova (Guy's and St. Thomas' NHS Trust)

    Group: NHS Genomic Medicine Centre
    Workplace: NHS clinical service

  • Arianna Tucci (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Pinki Munot (Consultant )

    Group: Other NHS organisation
    Workplace: NHS clinical service

46 Entities

41 reviewed, 17 green

List Entity Reviews Mode of inheritance Details
46 Entitiess
Green Green List (high evidence)
15q11q13 recurrent (PWS/AS) region (BP1-BP3, Class 1) Loss
ISCA-37404-Loss
Region
0 reviews
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • ClinGen
  • Expert Review Green
Phenotypes
  • microcephaly
  • 105833
  • Developmental delay, muscle weakness
  • Mental retardation
  • Angelman syndrome
  • 176270
  • Prader-Willi syndrome
Tags
Green Green List (high evidence)
2p15p16.1 region (includes BCL11A) Loss
ISCA-37408-Loss
Region
0 reviews
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • ClinGen
  • Expert Review Green
Phenotypes
  • PMID: 16963482 idiopathic intellectual disability including moderate to severe intellectual disability, autism/autistic features, microcephaly, structural brain anomalies including cortical dysplasia/pachygyria, renal anomalies (multicystic kidney, hydronephrosis), digital camptodactyly, visual impairment, strabismus, neuromotor deficits, communication and attention impairments, and a distinctive pattern of craniofacial features. Dysmorphic craniofacial features include progressive microcephaly, flat occiput, widened inner canthal distance, small palpebral fissures, ptosis, long and straight eyelashes, broad and high nasal root extending to a widened, prominent nasal tip with elongated, smooth philtrum, rounding of the upper vermillion border and everted lower lips. PMID: 18245392 A 32-year-old, mentally retarded male was referred to our centre for further clinical genetic analysis. He was born to non-consanguineous parents after 42 weeks gestation with a birth weight of 3500 g. He had a healthy older brother. In the neonatal period he was hypotonic and at 8 weeks of age he underwent surgery because of an inguinal hernia with removal of an atrophic right testis. His motor development was severely delayed with sitting at 3.5 years and walking at 5 years of age. Speech was poorly developed, characterised by the usage of only a few words. During infancy an optic nerve hypoplasia was diagnosed, and during childhood he frequently suffered from luxations of the patellae, which required surgery. At the age of 32 years his height is 163 cm (_3 SDS) and head circumference 52.5 cm (_2.5 SDS). He has a narrow receding forehead, widened inner canthal distance of 3.5 cm (90th centile), normal outer canthal distance of 8.5 cm (25th centile), telecanthus, short and down slanting palpebral fissures, epicanthal folds, ptosis, long, straight eyelashes, high nasal bridge, low set large ears, flat philtrum, small mouth with high, narrow palate and retrognathia. The thorax is broad with increased internipple distance and slight gynaecomastia. A recent renal ultrasound revealed multiple cysts in the left, dystrophic kidney and two uncomplicated cysts in the enlarged, right kidney. The patient has a normally sized phallus with absent right testis and small left testis. His hands show a simian crease right and tapering fingers with broad proximal interphalangeal joints. He shows sandal gaps on both flat feet with clinodactyly of the fourth and fifth toes (and more)
  • 612513
  • PMID: 22579565 severe developmental delay, congenital microcephaly, intractable epilepsy, and renal anomalies, as well as a congenital choledochal cyst which has not been previously reported in other patients with this cytogenetic defect
Tags
Green Green List (high evidence)
17q21.3 recurrent region (includes KANSL1) Loss
ISCA-37420-Loss
Region
0 reviews
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • ClinGen
  • Expert Review Green
Phenotypes
  • PMID: 18628315 developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour, other clinically important features include epilepsy, heart defects and kidney/urologic anomalies
  • 610443
  • PMID: 25217958
  • Koolen-De Vries syndrome 610443
Tags
Green Green List (high evidence)
4p16.3 terminal (Wolf-Hirshhorn syndrome) region Loss
ISCA-37429-Loss
Region
0 reviews
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • ClinGen
  • Expert Review Green
Phenotypes
  • 194190
  • Wolf-Hirschhorn syndrome
Tags
Green Green List (high evidence)
15q11q13 recurrent (PWS/AS) region (BP2-BP3, Class 2) Loss
ISCA-37478-Loss
Region
0 reviews
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • ClinGen
  • Expert Review Green
Phenotypes
  • microcephaly
  • Developmental delay, muscle weakness
  • Mental retardation
  • Angelman syndrome
  • 176270
  • Prader-Willi syndrome
  • 105830
Tags
Green Green List (high evidence)
AR
4 reviews
2 green
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Androgen insensitivity, 300068Spinal and bulbar muscular atrophy of Kennedy, 313200Androgen insensitivity, partial, with or without breast cancer, 312300{Prostate cancer, susceptibility to}, 176807Hypospadias 1, X-linked, 300633
Tags
  • currently-ngs-unreportable
  • nucleotide-repeat-expansion
Green Green List (high evidence)
AR_CAG
STR
2 reviews
1 green
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • Spinal and bulbar muscular atrophy or Kennedy diseases 313200
Tags
  • STR
Green Green List (high evidence)
ASAH1
2 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Spinal muscular atrophy with progressive myoclonic epilepsy, 159950
Tags
Green Green List (high evidence)
BICD2
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Spinal muscular atrophy, lower extremity-predominant, 2, AD, 615290 -3
Tags
Green Green List (high evidence)
CHCHD10
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Spinal muscular atrophy, Jokela type 615048
Tags
Green Green List (high evidence)
DMPK_CTG
STR
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • Myotonic dystrophy 1 160900
Tags
  • STR
Green Green List (high evidence)
DYNC1H1
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Spinal muscular atrophy, lower extremity-predominant, AD, 158600
Tags
Green Green List (high evidence)
EXOSC3
2 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Pontocerebellar hypoplasia, type 1B 614678
Tags
Green Green List (high evidence)
IGHMBP2
3 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • UKGTN
Phenotypes
  • Spinal muscular atrophy with respiratory distress, 604320
Tags
Green Green List (high evidence)
SLC52A2
4 reviews
3 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert list
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Brown-Vialetto-Van Laere syndrome 2, 614707
Tags
  • treatable
Green Green List (high evidence)
SLC52A3
3 reviews
3 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Brown-Vialetto-Van Laere syndrome 1, 211530
Tags
Green Green List (high evidence)
SMN1
4 reviews
3 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Spinal muscular atrophy-1, 253300
Tags
  • cnv
  • gene-therapy-trial
Green Green List (high evidence)
SPG11
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • UKGTN
Phenotypes
  • Amyotrophic lateral sclerosis 5, juvenile 602099
Tags
Green Green List (high evidence)
TRIP4
2 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Spinal muscular atrophy with congenital bone fractures 1 616866
Tags
Green Green List (high evidence)
TRPV4
3 reviews
2 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Distal Congenital Nonprogressive Spinal Muscular Atrophy
  • Brachyolmia type 3, 113500
Tags
Green Green List (high evidence)
UBA1
2 reviews
2 green
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Sources
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Infantile Spinal Muscular Atrophy, X-Linked
  • Spinal muscular atrophy, X-linked 2, infantile, 301830
Tags
Green Green List (high evidence)
VRK1
2 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Pontocerebellar hypoplasia type 1A 607596
Tags
Amber Amber List (moderate evidence)
ALS2
3 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Illumina TruGenome Clinical Sequencing Services
  • Literature
  • UKGTN
Phenotypes
  • juvenile amyotrophic lateral sclerosis-2, 205100
Tags
Amber Amber List (moderate evidence)
ATP7A
2 reviews
Not set
Sources
  • Expert
  • Expert Review Amber
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Menkes disease, 309400Occipital horn syndrome, 304150Spinal muscular atrophy, distal, X-linked 3, 300489
Tags
Amber Amber List (moderate evidence)
EXOSC8
3 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Literature
  • UKGTN
Phenotypes
  • Pontocerebellar hypoplasia, type 1C 616081
Tags
Amber Amber List (moderate evidence)
HSPB1
2 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert
  • Expert Review Amber
Tags
Amber Amber List (moderate evidence)
HSPB8
2 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert
  • Expert Review Amber
Phenotypes
  • Neuropathy, distal hereditary motor, type IIA 158590
Tags
Amber Amber List (moderate evidence)
REEP1
3 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
  • Literature
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • ?Neuronopathy, distal hereditary motor, type VB 614751
Tags
Amber Amber List (moderate evidence)
SETX
3 reviews
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Amyotrophic lateral sclerosis 4, juvenile 602433
Tags
Amber Amber List (moderate evidence)
VAPB
3 reviews
2 red
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Spinal muscular atrophy, late-onset, Finkel type 182980
  • Amyotrophic lateral sclerosis 8 608627
Tags
Red Red List (low evidence)
AARS
3 reviews
2 red
Not set
Sources
  • Expert
  • Expert Review Red
Tags
Red Red List (low evidence)
BSCL2
2 reviews
1 green
Not set
Sources
  • Expert
  • Expert Review Red
Tags
Red Red List (low evidence)
DCTN1
1 review
Not set
Sources
  • Expert
  • Expert Review Red
Tags
Red Red List (low evidence)
DMPK
2 reviews
1 red
Not set
Sources
  • Emory Genetics Laboratory
  • Expert Review Red
Phenotypes
  • spinal muscular atrophy, myotonic dystrophy (type 1), Prader-Willi syndrome, Angelman syndrome, and maternal UPD 14.
Tags
  • currently-ngs-unreportable
  • nucleotide-repeat-expansion
Red Red List (low evidence)
DNAJB2
1 review
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert
  • Expert Review Red
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Spinal muscular atrophy, distal, autosomal recessive, 5, 614881
Tags
Red Red List (low evidence)
FBXO38
1 review
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Neuronopathy, distal hereditary motor, type IID 615575
Tags
Red Red List (low evidence)
GARS
1 review
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert
  • Expert Review Red
  • Illumina TruGenome Clinical Sequencing Services
Phenotypes
  • Distal Spinal Muscular Atrophy
Tags
Red Red List (low evidence)
HSPB3
1 review
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert
  • Expert Review Red
Phenotypes
  • ?Neuronopathy, distal hereditary motor, type IIC 613376
Tags
Red Red List (low evidence)
MEG3
2 reviews
Not set
Sources
  • Expert Review Red
Tags
  • locus-type-rna-long-non-coding
Red Red List (low evidence)
PLEKHG5
1 review
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert
  • Expert Review Red
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Distal Spinal Muscular Atrophy
  • Spinal muscular atrophy, distal, autosomal recessive, 4, 611067
Tags
Red Red List (low evidence)
SIGMAR1
2 reviews
2 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Literature
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • ?Amyotrophic lateral sclerosis 16, juvenile 614373
Tags
Red Red List (low evidence)
SLC52A1
2 reviews
2 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • UKGTN
Tags
Red Red List (low evidence)
SLC5A7
2 reviews
2 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Literature
  • UKGTN
Phenotypes
  • Neuronopathy, distal hereditary motor, type VIIA 158580
Tags
Red Red List (low evidence)
SNRPN
4 reviews
1 red
Other - please specifiy in evaluation comments
Sources
  • Emory Genetics Laboratory
  • Expert Review Red
Phenotypes
  • Prader-Willi syndrome 176270
Tags
  • currently-ngs-unreportable
Red Red List (low evidence)
SYT2
2 reviews
Not set
Sources
  • Expert
  • Expert Review Red
Tags
Red Red List (low evidence)
UBQLN1
2 reviews
2 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Brown-Vialetto-Van Laere syndrome/ atypical motor neurone disease
Tags

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