Monogenic hearing loss
Gene: PMP22
Comment on list classification: After consultation with Genomics England clinical team leaving this gene as amber as the majority of patients do not have a hearing loss phenotype, and there are also issues around the potential predictive nature of the neurological aspects if this panel was applied to a paediatric hearing loss cohort.Created: 22 Dec 2020, 4:04 p.m. | Last Modified: 22 Dec 2020, 4:04 p.m.
Panel Version: 2.139
Comment on list classification: Promoting this gene from red to amber. Three independent cases reported in which patients have Charcot-Marie-Tooth disease plus hearing loss and variants in PMP22, but waiting for feedback from Genomics England clinical team as to whether this gene is appropriate to be green as HL is part of a syndrome of features.Created: 26 Nov 2020, 3:04 p.m. | Last Modified: 26 Nov 2020, 3:04 p.m.
Panel Version: 2.129
Associated with Charcot-Marie-Tooth disease, type 1E #118300 (AD) in which hearing loss is listed as a clinical feature
PMID: 12578939 - Sambuughin et al 2003 - report deafness associated with a demyelinating neuropathy in three individuals of a family in whom a novel 12bp deletion resulting in the deletion of four-amino acid deletion (115-118) in the PMP22 gene was identified (targeted sequencing of PMP22). No asymptomatic family members had the deletion nor was it detected in 55 healthy controls.
PMID: 11835375 - Boerkoel et al 2002 - screened PMP22, GJB1, and MPZ in 159 unrelated patients with primary peripheral demyelinating neuropathy or a primary peripheral axonal neuropathy and report 5 which have heterozygous variants in PMP22, 1 of which had a clinical diagnosis of CMT1 + deafness (variant 82T>C W28R). An affected sibling had the same variant.
PMID: 10330345 - Kovach et al 1999 - analysis of a 7 generation family from central Illinois with autosomal dominant CMT and deafness. In the 31 affected family members, hearing loss ranged from borderline normal to profound hearing loss, with all having at least mild bilateral hearing loss by adulthood. Following haplotype analysis they sequenced PMP22 and a point mutation was found in affected individuals G->C at position 248 in exon 4 in the heterozygous state (p.Ala67Pro).
PMID: 8355122 - Hamiel et al 1993 - Abstract only accessed. Describe a family with hereditary motor-sensory neuropathy with sensorineural deafness is described; the neurologic features and deafness were apparent in early childhood and infancy.
Summary: 3 cases in which hearing loss is reported in CMT patients with PMP22 variants. In all cases a limited number of genes were sequenced.Created: 4 Nov 2020, 10:52 a.m. | Last Modified: 26 Nov 2020, 2:52 p.m.
Panel Version: 2.125
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
CMT caused by variants in PMP22 has been described in association with deafness in a very small number of families. Specific variants may be responsible for the association (A67P, W28R and deletion of 4 amino acids: ala, ile, tyr, and thr, at positions 115-118)Created: 29 Jan 2020, 6:07 a.m. | Last Modified: 29 Jan 2020, 6:07 a.m.
Panel Version: 2.4
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Charcot-Marie-Tooth disease, type 1E 118300
Publications
Inheritance:?Autosomal dominant;Autosomal dominant;Autosomal recessiveCreated: 9 Feb 2016, 10:07 a.m.
Inheritance:Autosomal dominant;?Autosomal dominant;Autosomal recessiveCreated: 7 Feb 2016, 7:12 p.m.
Inheritance:?Autosomal dominant;Autosomal recessive;Autosomal dominantCreated: 7 Feb 2016, 4:55 p.m.
Inheritance:Autosomal dominant;Autosomal recessive;?Autosomal dominantCreated: 7 Feb 2016, 3:45 p.m.
Inheritance:Autosomal dominant,?Autosomal dominant,Autosomal recessiveCreated: 7 Feb 2016, 9:29 a.m.
Inheritance:Autosomal recessiveCreated: 7 Feb 2016, 9 a.m.
Mode of inheritance
Other
Phenotypes
#118220:Charcot-Marie-Tooth disease, type 1A[Kyphoscoliosis may occur; Claw hand deformities (in severe cases); Pes cavusHammer toesFoot deformities; Distal limb muscle weakness due to peripheral neuropathyDistal limb muscle atrophy due to peripheral neuropathy' Steppage' gaitFoot dropCold-induced muscle crampsDistal sensory impairmentHyporeflexiaAreflexiaDecreased motor nerve conduction velocity (NCV) (less than 38 m/s)Hypertrophic nerve changes' Onion bulb' formations on nerve biopsySegmental demyelination/remyelination on nerve biopsyDecreased number of myelinated fibersMyelin outfoldings may occur in a subset of patients]; #118300:Charcot-Marie-Tooth disease, type 1E[Sensorineural hearing loss; Claw hand deformities; Pes calcaneovarusPes cavusHammertoesFoot deformities; Distal limb muscle weakness due to peripheral neuropathyDistal limb muscle atrophy due to peripheral neuropathy' Steppage' gaitFoot dropPoor balanceDistal sensory impairmentHyporeflexiaAreflexiaDecreased motor nerve conduction velocity (NCV)]; #139393:Neuropathy, inflammatory demyelinating[Acute demyelinating polyneuropathy; Usually sporadic]; #145900:Dejerine-Sottas disease[Nystagmus (in some patients); Kyphoscoliosis may occur; Claw hand deformities (in severe cases); Pes cavusHammer toesFoot deformities; Delayed motor developmentHypotoniaDistal limb muscle weakness due to peripheral neuropathyDistal limb muscle atrophy due to peripheral neuropathy' Steppage' gaitFoot dropDistal sensory impairmentSensory ataxiaHyporeflexiaAreflexiaIncreased CSF proteinSeverely decreased motor nerve conduction velocity (NCV) (less than 38 m/s)Hypertrophic nerve changes' Onion bulb' formations on nerve biopsySegmental demyelination/remyelination on nerve biopsyDecreased number of myelinated fibers]; #162500:Neuropathy, recurrent, with pressure palsies[Peroneal muscle weakness, transient, recurrent due to peripheral neuropathyRadial, ulnar, and median nerve muscles may be affectedVocal cord paralysis has been reportedHyporeflexiaTomacula (sausage-shaped swellings of the myelin sheath) on nerve biopsySegmental demyelination/remyelination on nerve biopsyDecreased motor nerve conduction velocities (NCV)]; #180800:Roussy-Levy syndrome[Kyphoscoliosis may be present; Pes cavusHammer toesFoot deformities; Delayed motor developmentDistal limb muscle weakness due to peripheral neuropathyDistal limb muscle atrophy due to peripheral neuropathyAtaxic gaitDistal sensory impairmentAreflexiaHyporeflexiaUpper limb postural tremorUpper limb action tremorDecreased motor nerve conduction velocity (NCV) (less than 20 m/s)Segmental demyelination/remyelination on nerve biopsyDecreased number of myelinated fibersHypertrophic nerve changes' Onion bulb' formations may be present; Foot ulcerationsFoot infections leading to amputation]
Publications
Gene: pmp22 has been classified as Amber List (Moderate Evidence).
Gene: pmp22 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: PMP22 were changed from to Charcot-Marie-Tooth disease, type 1E OMIM:118300; Charcot-Marie-Tooth disease type 1E MONDO:0007311
Publications for gene: PMP22 were set to
Mode of inheritance for gene: PMP22 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
PMP22 was added to Congenital hearing impairment (Profound/Severe)panel. Sources: Expert