With this work we would like to highlight the challenges posed by NGS in interpreting novel variants. The described patient had variants in SACS and APTX, two genes with partially overlapping phenotypes. For both she has an atypical, late onset, but only a diagnosis of ARSACS can be performed with certainty, due to the presence of a pathogenic variant in homozygosity.
This case illustrates one of the limitations of NGS techniques, as it can have results that physicians may have a hard time interpreting. However, it also shows one of its benefits, because one of these diagnoses would likely be missed if NGS techniques weren’t being used.
Just like in this case, there have been other case reports of NGS techniques being applied either for the same purpose, or for another. Whatever the context is, it’s important to understand that these studies, just like every other exam, have drawbacks that clinicians should be familiar with in order to reduce the drawbacks of using this powerful tool.
Finally, this is the first report of the likely pathogenic variant c.4521_4522del(p.(Asn1508Serfs*32)) in SACS.
21
T ABLES
Table I – Patients with neurological disorders and pathogenic variants in two or more genes
Legend: MELAS - Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes; HSP – hereditary spastic paraplegia; LGMD2H/STM – limb-girdle muscular dystrophy type 2H/
sarcotubular myopathy; ARSACS - Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay; TSC – Tuberous Sclerosis Complex; CMT2 - Charcot-Marie-Tooth disease type 2; CFTD – congenital fiber-type disproportion; ALS - Amyotrophic Lateral Sclerosis; BBS - Bardet-Biedl Syndrome; VUS – variants of unknown significance
Article and nº of patients
Disease Symptoms/ Signs Genetic variants Diagnostic changes
post-NGS
Benefit of NGS
Hannah-Shmouni, F., et al38 [2021]
(8 patients)
Myotonic dystrophy type 1
• Posterior cataracts
• Handgrip weakness
• Myotonia
• Scapular winging
• Full/ Everted lips
• 800 CTG repeats in the DMPK gene
• A deleted fragment in the D4Z4 macrosatellite
A concomitant diagnosis of myotonic dystrophy type 1 and fascioscapulohumeral muscular dystrophy type 1 was made
To find a second diagnosis
Hannah-Shmouni, F., et al38 [2021]
(8 patients)
MELAS • Worsening muscle fatigability and weakness
• Atrophy of the right pectoralis
• High riding scapula with arm abduction
• Asymmetric weakness and atrophy of the periscapular muscles
• m.3243A>G
• A deleted fragment in the D4Z4 macrosatellite
A concomitant diagnosis of
MELAS and
fascioscapulohumeral muscular dystrophy type 1 was made
To find a second diagnosis
22 Table I (continued)
Article and nº of patients
Disease Symptoms/ Signs Genetic variants Diagnostic changes
post-NGS
Benefit of NGS
Hannah-Shmouni, F., et al38 [2021]
(8 patients)
Becker muscular dystrophy
• Mild bilateral calf pseudohypertrophy
• Premature birth (32 weeks) with macrosomia
• Pregnancy complicated by polyhydramnios
• Undescended testis and umbilical hernia during childhood
• Obesity
• Pit on the right ear
• Crease on the left ear
• Macroglossia
• Hemizygous in-frame deletion of exons 45-48 of the DMD gene
• Hypometilation at IC2 of
the maternal
chromossome
A concomitant diagnosis of Becker muscular dystrophy and Beckwith-Wiedemann syndrome was made
To find a second diagnosis
Hannah-Shmouni, F., et al38 [2021]
(8 patients)
Duchenne muscular dystrophy
• Mild proximal weakness
• Bilateral calf pseudohypertrophy
• Single-touch Gower’s maneuver
• Mild waddling gait
• Stiffness since birth
• Falls without defensive posturing
• An exaggerated startle response
• Awakening with significant seizure-like shaking
• Positive nose tapping test
• DMD deletion of exons 8-47
• Pathogenic variant in exon 8 of the GLRA1 gene (c.920A > G, p.
Tyr307Cys)
A concomitant diagnosis of Duchenne muscular
dystrophy and
hyperekplexia was made
To find a second diagnosis
23 Table 1 (continued)
Article and nº of patients
Disease Symptoms/ Signs Genetic variants Diagnostic changes
post-NGS
Benefit of NGS
Hannah-Shmouni, F., et al38 [2021]
(8 patients)
Myotonic dystrophy type 1
• Hypotonia
• Intellectual disability disproportionate to the diagnosis of myotonic dystrophy type 1
• 800 CTG repeats in the DMPK gene
• Partial deletion of NRXN1 gene
A concomitant diagnosis of myotonic dystrophy type 1 and microdeletion syndrome involving NRXN1 was made
To find a second diagnosis
Hannah-Shmouni, F., et al38 [2021]
(8 patients)
Myotonic dystrophy type 1
• Global development delay
• History of seizures
• Low vision
• Congenital heart defects (coarctation of the aorta and atrial and ventricular sept defects)
• Multiple dysmorphic facial features
• Short stature
• Clinodactyly
• Brachydactyly
• <500 CTG repeats in the DMPK gene
• Two de novo microdeletions on chromosome 1
A concomitant diagnosis of mild myotonic dystrophy type 1 and microdeletion syndrome was made
To find a second diagnosis
Hannah-Shmouni, F., et al38 [2021]
(8 patients)
Duchenne muscular dystrophy
• Modified Gower maneuver
• Global development delay preceding the onset of typical features of Duchenne muscular dystrophy
• Wheelchair use at the age of 8
• Pathogenic variant in exon 70 of the DMD gene
• Duplication at 1q21.1q21.2
A concomitant diagnosis of Duchenne muscular dystrophy and 1q21.1 microduplication syndrome was made
To find a second diagnosis
24 Table I (continued)
Article and nº of patients
Disease Symptoms/ Signs Genetic variants Diagnostic changes
post-NGS
Benefit of NGS
Hannah-Shmouni, F., et al38 [2021]
(8 patients)
Spinocerebellar ataxia type 14
• Development delay
• Intellectual disability
• Spasticity
• Upgoing toes
• Ataxia
• Dysmorphic facial features
• Pathogenic variant in the PRKGC gene
• Partial deletion of the SOX5 gene
A concomitant diagnosis of spinocerebellar ataxia type 14 and Lamb-Shaffer syndrome was made
To find a second
diagnosis
Hata, Y., et al39 [2020], (2 patients)
Dravet syndrome • Mild development delay
• Frequent seizures
• Novel variant in intron 23 of SCN1A gene
• Heterozygous for two variants in the CNTNAP2 gene
• MYBPC3_T1046M
• CETP_c.1146 + 1G > A
• TCAP_E49K
• Concomitant diagnosis of Dravet syndrome
and recessive
symptomatic focal epilepsy with mental retardation was made
• Identification of variants associated with increased risk of hypertrophic
cardiomyopathy, dilated cardiomyopathy and cholesterol ester transfer protein deficiency (the patient died before the age of disease onset)
• To find a second diagnosis
• To find variants associated with other diseases
25 Table I (continued)
Article and nº of patients
Disease Symptoms/ Signs Genetic variants Diagnostic changes
post-NGS
Benefit of NGS
Hata, Y., et al39 [2020], (2 patients)
Dravet syndrome Frequent febrile seizures • Missense variant in SCN1A
• ZMPSTE24_L438F
• SYNE2_T5138M
Increased risk of metabolic disease and dilated cardiomyopathy and Emery-Dreifuss muscular dystrophy-5 (the patient died before the age of disease onset)
To find variants associated with other diseases
Wayhelova, M., et al40 [2020] (2 patients)
Biotinidase deficiency
• Intelectual disability with autistic features
• Microcephaly
• Cortical blindness
• Central hypotonia
• Refractory atonic seizures
• Hemizygous for a deletion in exon 5 of the IQSEC2 gene
• Heterozygous
pathogenic variant in the BTD gene
A concomitant diagnosis of biotinidase deficiency and non-syndromic X-linked intellectual development disorder-1
To find a second diagnosis
Wayhelova, M., et al40 [2020] (2 patients)
Biotinidase deficiency
• Intelectual disability
• Central hypotonia
• Strabismus
• Refractory atonic and myoclonic seizures
• Hemizygous for a deletion in exon 5 of the IQSEC2 gene
• Heterozygous
pathogenic variant in the BTD gene
A concomitant diagnosis of biotinidase deficiency and non-syndromic X-linked intellectual development disorder-1
To find a second diagnosis
Wiedemann, A., et al41 [2020] (2 patients)
HSP • Spastic paraplegia
• Hyperreflexia
• Bilateral extensor plantar responses
• Cognitive impairment
• Compound heterozygous variants in MTHFR
• Two rare pathogenic variants in POLG
A concomitant diagnosis of MTHFR deficiency and a POLG-related syndrome was made
To find a second diagnosis
26 Table I (continued)
Article and nº of patients
Disease Symptoms/ Signs Genetic variants Diagnostic changes
post-NGS
Benefit of NGS
Wiedemann, A., et al41 [2020] (2 patients)
HSP • Spastic paraplegia
• Hyperreflexia
• Bilateral extensor plantar responses
• Cognitive impairment
• Compound
heterozygous variants in MTHFR
• Two rare pathogenic variants in POLG
A concomitant diagnosis of MTHFR deficiency and a POLG-related syndrome was made
To find a second
diagnosis
Marttila, M., et al42 [2019]
(1 patient)
Congenital myopathy
• Generalized hypotonia
• Diminished reflexes
• Muscle weakness
• Homozygous for a pathogenic variant in MYL2
• Heterozygous for a pathogenic variant in NEB
• Heterozygous for a benign variant in the TTN gene
• Hemizygous for a likely benign variant in the DMD gene
A diagnosis of CFTD and
infantile onset
cardiomyopathy associated with pathogenic variants in the MYL2 gene was made
To find a second
diagnosis
27 Table I (continued)
Article and nº of patients
Disease Symptoms/ Signs Genetic variants Diagnostic changes
post-NGS
Benefit of NGS
Dangiolo, S.B., et al43 [2015] (1 patient)
Clinically diagnosed Bohring-Opitz syndrome
• Neurodevelopment delay
• Failure to thrive
• Pharyngeal dysphagia
• Gastro-esophageal reflux
• Severe scoliosis
• Abnormal uterine bleeding
• Severe recurrent acute pancreatitis
• Microcephaly
• Dysmorphic facial features
• Hypermobile joints
• Flexion contractions in the distal parts of all limbs
• Tremor
• Choreiform movements
• A frameshift variant in the ASXL1 gene
• Compound
heterozygosity in the CFTR gene
A concomitant diagnosis of Bohring-Opitz syndrome and cystic fibrosis was made
To find a second diagnosis
Moteki, H., et al44
[2015] (2
patients)
MELAS • Progressive bilateral
neurosensorial hearing loss
• Diabetes mellitus
• Hypertrophic cardiomyopathy
• Overweight
• Short stature
• mtDNA 3243A>G variant
• Missense variant in the P2RX2 gene
A concomitant diagnosis of MELAS and autosomal dominant deafness-41 was made
To find a second diagnosis
28 Table I (continued)
Article and nº of patients
Disease Symptoms/ Signs Genetic variants Diagnostic changes
post-NGS
Benefit of NGS
Moteki, H., et al44 [2015] (2 patients)
MELAS • Progressive bilateral
neurosensorial hearing loss
• Diabetes mellitus
• Hypertrophic cardiomyopathy
• Mental retardation
• Overweight
• Short stature
• mtDNA 3243A>G variant
• Missense variant in the P2RX2 gene
A concomitant diagnosis of MELAS and autosomal dominant deafness-41 was made
To find a second
diagnosis
Nectoux, J., et al45 [2015] (2 patients)
Non identified limb-girdle
muscular dystrophy
• Pelvic and lower-limb muscular weakness associated with atrophy
• Lower-limb arreflexia
• Distal upper-limb atrophy
• Cognitive impairment
• Homozygous deletion of the whole TRIM32 gene
• Homozygous partial deletion of the ASTN2 gene
A concomitant diagnosis of
LGMD2H/STM and
cognitive impairment related to ASTN2 was made
To find a second
diagnosis
Nectoux, J., et al45 [2015] (2 patients)
Non identified limb-girdle
muscular dystrophy
• Progressive muscle weakness with frequent falls
• Scapular winging
• Waddling gait
• Heterozygous
deletion of the whole TRIM32 gene
• Heterozygous partial deletion of the ASTN2 gene
A diagnosis of
LGMD2H/STM was made
To find a second
diagnosis
Li, L., et al46 [2019] (1 patient)
Phenylketonuria • Generalized hypotonia
• Hearing loss
• External ophthalmoplegia
• Pronated feet
• Mental retardation
• Delayed development
• Compound
heterozygous in the PAH gene
• Compound
heterozygous in the POLG gene
The patient’s phenotype was explained by concomitant
phenylketonuria and POLG-related syndrome
To find
variants in multiple genes that explain the phenotype
29 Table I (continued)
Article and nº of patients
Disease Symptoms/ Signs Genetic variants Diagnostic changes
post-NGS
Benefit of NGS
Lal, D., et al47 [2016] (2 patients)
Hereditary
hypophosphatemic rickets
• Muscular weakness
• Delayed motor milestones
• Muscular hypotonia
• Rigid spine
• Short stature
• X-legs
• Respiratory failure
• Homozygous variants in SEPN1
• Homozygous variants in SLC34A3
The patient’s phenotype was explained by concomitant recessive SEPN1 and SLC34A3 disease
To find
variants in multiple genes that explain the phenotype
Lal, D., et al47 [2016] (2 patients)
Hereditary
hypophosphatemic rickets
• Muscular weakness
• Muscular hypotonia
• X-legs
• Homozygous variants in SEPN1
• Homozygous variants in SLC34A3
The patient’s phenotype was explained by concomitant recessive SEPN1 and SLC34A3 disease
To find
variants in multiple genes that explain the phenotype
30 Table I (continued)
Article and nº of patients
Disease Symptoms/ Signs Genetic variants Diagnostic changes
post-NGS
Benefit of NGS
Cordova-Fletes, C., et al48 [2018] (1 patient)
Brain anomalies and skeletal dysplasia of unknown origin
• Mental retardation
• Short stature
• Microcephaly
• Pulmonary valve stenosis
• Kyphoscoliosis
• Seizures
• Chronic constipation
• Generalized hypertonia
• Generalized hyperreflexia
• Multiple dysmorphic facial features
• Micropenis
• Phimosis
• Cryptorchidism
• Shawl scrotum
• Short hands
• Brachysyndactyly
• Symphalangism
• Homozygous likely pathogenic variant in the SPAG17 gene
• Homozygous VUS in the WDR35 gene
• VUS microduplication of the NXPH3 gene
The patient’s phenotype was explained by concomitant SPAG17 and WDR35 related disease
To find variants in multiple genes that explain the phenotype
Klimkowicz-Mrowiec, A., et al49 [2021]
(2 patients)
Frontal variant of Alzheimer’s disease
• Apathy
• Episodic memory impairment
• Executive dysfunction
• Rare polymorphism in the PSEN2 gene
• Pathogenic variant in the GRN gene
The diagnosis was changed from frontal variant of Alzheimer’s disease to frontotemporal dementia
To find variants in multiple genes that explain the phenotype
31 Table I (continued)
Article and nº of patients
Disease Symptoms/ Signs Genetic variants Diagnostic changes
post-NGS
Benefit of NGS
Klimkowicz-Mrowiec, A., et al49 [2021]
(2 patients)
Frontal variant of Alzheimer’s disease
• Apathy
• Episodic memory impairment
• Executive dysfunction
• Rare polymorphism in the PSEN2 gene
• Pathogenic variant in the GRN gene
The diagnosis was changed from frontal variant of Alzheimer’s disease to frontotemporal dementia
To find variants in multiple genes that explain the phenotype
Manzanilla-Romero, H.H., et al50 [2021]
(1 patient)
Clinical
suspicion of TSC
• Round, well-circumcised, 1 mm in diameter, confluent papules in the nasal and paranasal regions
• Fatty liver disease
• Single retinal hamartoma in the right eye
• Subependymal giant cell astrocytoma
• Hyperintense cortical tubers
• Heterozygous for a variant in the TSC2 gene
• Deletion of exons 30 and 40 of the PDK1 gene
A diagnosis was made of somatic mosaicism of PDK1/TSC2-microdeletion (contiguous-gene
syndrome)
• To find variants associated with other diseases
• To find variants in multiple genes that explain the phenotype Fabrizi, G.M.,
et al51 [2020]
(3 patients)
Unidentified mild
predominantly sensory axonal polyneuropathy
• Muscle cramps in her legs and hands
• Mild pes cavus
• Mild interosseus muscle wasting
• Heterozygous
missense variant in the TFG gene
• Heterozygous
missense variant in the DCTN2 gene
After comparison of the patient’s genotype and phenotype with the ones from other family members (affected and healthy), it was concluded the TFG gene variant was responsible for the neurological symptoms
To find variants in multiple genes that explain the phenotype
32 Table I (continued)
Article and nº of patients
Disease Symptoms/ Signs Genetic variants Diagnostic changes
post-NGS
Benefit of NGS
Fabrizi, G.M., et al51 [2020]
(3 patients)
Unidentified motor-sensory axonal
neuropathy
• Claw hands
• Sensory gait ataxia
• Weakness of forearm muscles
• Touch allodynia and loss of vibration sense with stocking-and-glove distribution
• Reduced/Absent deep tendon reflexes
• Dysphagia
• Muscle cramps in all limbs
• Paroxysmal unilateral facial pain
• Heterozygous
missense variant in the TFG gene
• Heterozygous
missense variant in the DHTKD1 gene
• Heterozygous
missense variant in the DCTN2 gene
After comparison of the patient’s genotype and phenotype with the ones from other family members (affected and healthy), it was concluded the TFG gene variant was responsible for the neurological symptoms
To find variants in multiple genes that explain the phenotype
Fabrizi, G.M., et al51 [2020]
(3 patients)
CMT2 • Wasting and weakness of the distal muscles of all limbs
• Sensory loss with stocking-and-glove distribution
• Heterozygous
missense variant in the TFG gene
• Heterozygous
missense variant in the DHTKD1 gene
After comparison of the patient’s genotype and phenotype with the ones from other family members (affected and healthy), it was concluded the TFG gene variant was responsible for the neurological symptoms
To find variants in multiple genes that explain the phenotype
33 Table I (continued)
Article and nº of patients
Disease Symptoms/ Signs Genetic variants Diagnostic changes post-NGS
Benefit of NGS
Melchionda, L., et al52 [2013] (1 patient)
Primary lateral sclerosis
• Spastic tetraparesis
• Bilateral atrophy of the temporalis, interosseous and anterior tibialis muscles
• Hypophonia
• Dysphagia
• Heterozygous variant in exon 7A of the GFAP gene
• Hemizygous for a variant in the HDAC6 gene
• The diagnosis was changed from primary lateral sclerosis to adult-onset
Alexander’s disease
• It was speculated that the HDAC6 variant influenced the phenotype
• To find variants in multiple genes that explain the phenotype
• To
understand the impact of a variant in a gene not directly associated with the disease Maselli, R.A.,
et al53 [2014]
(1 patient)
Unknown limb-girdle
myasthenia
• Waddling gait
• Facial weakness without eyelid and ocular involvement
• Neck, proximal limb, wrist extension and foot dorsiflexion muscular weakness
• Hyporeflexia
• Worsening of the symptoms at the end of the day
Variants in the following genes: GFPT1, NEB, BIN1, DYSF, GNE, SYNE1 and COL6A3
A diagnosis of congenital myasthenic syndrome 12 was made
To find variants in multiple genes that explain the phenotype
34 Table I (continued)
Article and nº of patients
Disease Symptoms/ Signs Genetic variants Diagnostic changes post-NGS
Benefit of NGS
Delmiro, A., et al54 [2013] (1 patient)
West syndrome
• Infantile spasms
• Seizures
• Behavioral changes
• Cognitive impairment
• Variant in the mtDNA gene MT-CO2
• Variant in the mtDNA gene MT-ND1
The diagnosis was changed from West syndrome to Lennox-Gastaut syndrome
To find variants in multiple genes that
explain the
phenotype Coussa, R.G.,
et al55 [2013]
(1 patient)
Autosomal recessive retinitis pigmentosa
• Reduced visual acuity
• Cognitive impairment
• Sub-clinical large exophytic renal cyst
• Splice site variant in TMEM5
• Missense variant in AIFM3
• Homozygous missense variant in WDR19
Senior-Loken syndrome-8 was diagnosed
To find variants in multiple genes that
explain the
phenotype
Armour, C.M., et al56 [2016]
(1 patient)
Fitzsimmons Syndrome
• Progressive spasticity
• Dysarthria
• Nasal speech
• Cone-shaped epiphyses
• Broad first digits
• Brachydactyly
• Pectus carinatum
• Compound
heterozygous in the SACS gene
• Nonsense variant in the TRPS1 gene
“Fitzsimmons syndrome”
was dropped and the patient was diagnosed with
ARSACS and
trichorhinophalangeal syndrome type 1
To break down a polygenic syndrome
into various
monogenic diseases
Marchese, M., et al58 [2016]
(2 patients)
Autism-epilepsy phenotype with
macrocephaly
• Autism-spectrum disorder
• Seizures
• Macrocephaly
• Variant in SNTA1
• Variant in DLG1
No changes, but a better understanding of the genetic basis of autism-spectrum disorder and its association with epilepsy and macrocephaly was achieved
To better understand the genetic basis of a multifactorial disease
35 Table I (continued)
Article and nº of patients
Disease Symptoms/ Signs Genetic variants Diagnostic changes post-NGS Benefit of NGS
Marchese, M., et al58 [2016] (2 patients)
Autism-spectrum disorder
Simple autism-spectrum disorder • Variant in STXBP1
• Variant in DLG1
No changes, but a better understanding of the genetic basis of autism-spectrum disorder and its association with epilepsy and macrocephaly was achieved
To better understand the genetic basis of a multifactorial disease
Azakli, H., et al59 [2013] (1 patient)
Hippocampal sclerosis
• Refractory epilepsy
• Mental retardation
• Epigastric auras
• Left hand automatisms
• Dystonic posture in the right hand
• Variant T16223C in the MT-HV1 gene
• Variant 3563 ins>C in the MT-ND1 gene
No changes, but a better understanding of the genetic basis of hippocampal sclerosis was achieved
To better understand the genetic basis of a multifactorial disease
Chakrabarty, S., et al60 [2020] (2 patients)
BBS • Learning difficulties
• Hypodactyly
• Retinal pigmented lesions
• Homozygous missense variant in BBS10 gene
• Hemizygous missense variant in AR gene
• Hemizygous missense variant in PDE6B gene
No changes, but the following associations were made:
• AR gene variants and androgen insensitivity syndrome
• PDE6B gene variants and retinitis pigmentosa
To better understand genotype-phenotype correlations in polygenic diseases
36 Table I (continued)
Article and nº of patients
Disease Symptoms/ Signs Genetic variants Diagnostic changes
post-NGS
Benefit of NGS
Chakrabarty, S., et al60 [2020] (2 patients)
BBS • Delayed development
milestones
• Emotional lability
• Visual impairment
• Acanthoses nigricans
• Post-axial polydactyly
• Right beat nystagmus
• Retinal pigmented lesions
• Single testis
• Micropenis
• Hypoplastic prostate and left seminal vesicle
• Homozygous missense variant in BBS10 gene
• Hemizygous missense variant in AR gene
• Hemizygous missense variant in PDE6B gene
No changes, but the following associations were made:
• AR gene variants and androgen insensitivity syndrome
• PDE6B gene variants and retinitis pigmentosa
To better understand genotype-phenotype correlations in polygenic diseases
Beigi, F., et al61 [2021] (1 patient)
BBS • Polydactyly
• Night blindness
• Peripheral vision loss
• Nystagmus
• Obesity
• Kidney failure
• Hyperpigmentation in retinal areas
• Bilateral pale optic discs
• Foveal reflex abnormalities
• Homozygous missense variant in the exon 5 of MKKS gene
• Homozygous missense variant in the exon 35 of the CEP290 gene
No changes, but by comparing the genotype of all sisters, the following conclusions about CEP290 gene variants were made:
• Association with a more severe BBS phenotype
• They aren’t enough to cause a disease without variants in other genes
To better understand genotype-phenotype correlations in polygenic diseases
37 Table I (continued)
Article and nº of patients
Disease Symptoms/ Signs Genetic variants Diagnostic changes
post-NGS
Benefit of NGS
Uittenbogaard, M., et al62 [2019] (2 patients)
MELAS • Multiple stroke-like episodes
• Seizures
• Mild ataxia with unsteady gait
• Occasional headaches
• Tinnitus
• Muscular weakness in all limbs
• Tremor that worsens with movement
• Ankle clonus
• Loss of peripheral vision
• Decreased upgaze
• Chronic renal failure
• m.1630A>G in the mitochondrial encoded MT-TV gene
• Heterozygous VARS2 pathogenic variant
• Other 9 heterozygous variants classified as VUS, likely pathogenic or pathogenic
No changes, but it was speculated that the VARS2 variant is responsible for a change in MELAS phenotype
To understand the impact of a variant in a
gene not
directly
associated with a certain disease
Uittenbogaard, M., et al62 [2019] (2 patients)
None • Asymptomatic • M.1630A>G in the
mitochondrial encoded MT-TV gene
• Heterozygous
pathogenic variant in the C8B gene
• Heterozygous VUS in the PRB3 gene
No changes, but by comparing the patient’s phenotype and genotype with the ones from her daughter, it was speculated that the VARS2 variant is responsible for a change in MELAS phenotype
To understand the impact of a variant in a
gene not
directly
associated with a certain disease