Genetic insights into PHARC syndrome: identification of a novel frameshift mutation in ABHD12

Daneshi, Ahmad; Garshasbi, Masoud; Farhadi, Mohammad; Falavarjani, Khalil Ghasemi; Vafaee-Shahi, Mohammad; Almadani, Navid; Zabihi, MohammadSina; Ghalavand, Mohammad Amin; Falah, Masoumeh

doi:10.1186/s12920-023-01682-w

BMC Medical Genomics

Table 1 Summary of the reported ABHD12 mutations in associated with PHARC syndrome

From: Genetic insights into PHARC syndrome: identification of a novel frameshift mutation in ABHD12

Nucleotide change*	AA change	E I	Mutation type	Age Sex	Poly neuropathy	Motor Neuropathy	HL	RP	ERG	Cataract	Ataxia	MR CT	Pyramidal Tract Signs	Other	Country	Family case	Ref
14 kb deletion removing exon 1		E1	Deletion	24 M	Abnormal	Pes cavus; absent tendon reflexes	14y Deaf	20y	NR	15y	Mild	Normal	Indifferent plantar response	No	UAE	6.1	[7]
14 kb deletion removing exon 1		E1	Deletion	20 M	Demyelinating polyneuropathy	Pes cavus; absent tendon reflexes	6y	Yes	NR	Yes	Speech and limb ataxia; wheelchair-bound (10y)	Cerebellar atrophy 3y	Extensor plantar response	No	UAE	6.2	[7]
14 kb deletion removing exon 1		E1	Deletion	6 F	NR	Absent tendon reflexes	Yes	No	NR	Yes	Speech and limb	Cerebellar atrophy	Indifferent plantar response	No	UAE	6.3	[7]
c.193 C > T	p.Arg65*	E2	Nonsense	55 F	No	No	17y 35y CI	Yes	Rod-cone abnormal	Yes	Ataxic gait with poor tandem walking; action tremor with writing cramp and involuntary athetotic movements of her fingers	Normal	NR	Night blindness, glaucoma	Lebanese	II.1	[41]
c.193 C > T	p.Arg65*	E2	Nonsense	53 M	NR	NR	24y 35y CI	Yes	NR	Posterior subcapsular cataract	NR	NR	NR	Glaucoma; severe optic atrophy	Lebanese	II.4	[41]
c.193 C > T	p.Arg65*	E2	Nonsense	22 M	Yes	7y; Lack of coordination	No	Yes	Rod-cone dystrophy	No	NR	NR	NR	No	NR	ABHD12-3 H-10	[34][8]
c.211-223del	p.Arg71Tyrfs*26	E2	Frameshift	42 M	Demyelinating polyneuropathy	Pes cavus; hammertoes; sensory loss;	43y bilaterally CI	Yes	Rod-cone dystrophy	38y	Wide-base gait, action tremor in the upper limbs	Mild cerebellar atrophy	NR	muscle MRI revealed mild fatty infiltration in the intrinsic muscles of both feet and the anterior compartment of the left leg	Spanish	II.3	[37]
c.211-223del	p.Arg71Tyrfs*26	E2	Frameshift	NR M	Demyelinating polyneuropathy	Pes cavus; hammertoes; sensory loss	18y	Yes	NR	Yes	Wide-base gait; dysarthria; slight dysmetria	Mild cerebellar atrophy	NR	No	Spanish	II.1	[37]
c.249 C > G	p.Tyr83*	E2	Nonsense	41 M	NR	NR	32y progressive	Yes	Abnormal	Yes	NR	NR	NR	Olfactory decline	China	I.1	[36]
c.249 C > G	p.Tyr83*	E2	Nonsense	31 M	NR	NR	32y progressive	Yes	NR	Yes	NR	NR	NR	Olfactory decline	China	II.5	[36]
c.259 C > A c.1063 C > T	p. Pro87Thr p.Arg355*	E2 E12	Missense Nonsense	28 F	NR	NR	No	Yes	Rod-cone dystrophy	No	No	NR	NR	No	NR	ABHD12-2	[34]
c.316 + 2T > A		I2	Splice site	56 M	Yes	Sensory loss	15y 41y CI	22y	NR	Yes	Steppage gait	Normal	NR	No	Japan	KTM 5012	[39]
c.316 + 2T > A		I2	Splice site	64 M	NR	NR	Progressive	45y	NR	Yes	NR	Cerebral and cerebellar atrophy	NR	Epilepsy; 30y night blindness	Japan	SNS5547	[39]
c.316 + 2T > A		I2	Splice site	NR M	NR	NR	Deaf	Yes	NR	Yes	NR	NR	NR	Epilepsy	Japan	SNS5548	[39]
c.319delA c.605 C > T	p.Arg107Glufs*8 p.Thr202Ile	E3 E6	Frameshift Missense	78 F	No	Decreased vibration sense in lower limbs	Presbycusis	Yes	NR	Yes	No	Minimal cerebral atrophy	No	No	Spain	1292-II.4	[40]
c.319delA c.605 C > T	p.Arg107Glufs*8 p.Thr202Ile	E3 E6	Frameshift Missense	75 M	No	Slightly loss of strength right upper limb	Presbycusis	Yes	NR	Yes	Dysmetria in lower limbs; slightly wide basegait	Normal	No	No	Spain	1292-II.5	[40]
c.319delA c.605 C > T	p.Arg107Glufs*8 p.Thr202Ile	E3 E6	Frameshift Missense	72 F	No	No	NR	Yes	NR	Yes	Gait somewhat unstable	NR	No	No	Spain	1292-II.6	[40]
c.319delA c.605 C > T	p.Arg107Glufs*8 p.Thr202Ile	E3 E6	Frameshift Missense	66 M	No	No	Presbycusis	Yes	Diminished	Yes	Slight dysarthria; mild distal postural tremor	Normal	No	No	Spain	1292-II.7	[40]
c.337-338delGAinsTTT	p.Asp113Phefs*15	E3	Frameshift	62 F	Demyelinating polyneuropathy	38y; pes cavus; sensory loss; absent ankle reflexes	20y	38y	Rod-cone dystrophy	28y	No	Normal	No	No	Norway	1.1	[7]
c.337-338delGAinsTTT	p.Asp113Phefs*15	E3	Frameshift	56 M	Demyelinating polyneuropathy	37y; pes cavus	30y	37y	Rod-cone dystrophy	37y	37y; gait ataxia	Normal	Extensor plantar response at lower limbs; spasticity; hyperreflexia	No	Norway	1.2	[7]
c.337-338delGAinsTTT	p.Asp113Phefs*15	E3	Frameshift	46 M	Demyelinating polyneuropathy	38y; distal sensory loss	Yes	46y	Rod-cone dystrophy	25y	43y; gait ataxia; upper limb intention tremor	Cerebellar atrophy	Extensor plantar response at lower limbs; spasticity; hyperreflexia	No	Norway	1.3	[7]
c.337-338delGAinsTTT	p.Asp113Phefs*15	E3	Frameshift	58 M	Demyelinating/ axonal polyneuropathy	51y; pes cavus; sensory loss; reduced tendon reflexes	20y	35y	Rod-cone dystrophy	26y	No	Cerebellar atrophy	Extensor plantar response at lower limbs	No	Norway	2.1	[7]
c.337-338delGAinsTTT	p.Asp113Phefs*15	E3	Frameshift	54 F	Yes	53y; pes cavus; reduced tendon reflexes	20y	25y	Flat	25y	No	NR	No	NO	Norway	2.2	[7]
c.337-338delGAinsTTT	p.Asp113Phefs*15	E3	Frameshift	36 F	Demyelinating polyneuropathy	Pes cavus; reduced tendon reflexes in lower limbs	10y Deaf	36y	Rod-cone dystrophy	32y	Yes	Atrophy of vermis and medulla oblongata	Extensor plantar response at right side; spasticity	No	Norway	3.1	[7]
c.337-338delGAinsTTT	p.Asp113Phefs*15	E3	Frameshift	24 M	Demyelinating polyneuropathy	Pes cavus; hammertoes; reduced tendon reflexes in upper and lower limbs	Yes	No	Normal	15y	No	Slight ventricular asymmetry	Indifferent plantar response	No	Norway	4.1	[7]
c.337-338delGAinsTTT	p.Asp113Phefs*15	E3	Frameshift	16 M	Demyelinating polyneuropathy	Pes cavus; reduced sensibility; reduced tendon reflexes in upper limbs, absent in lower limbs	13y	No	Normal	16y slight	No	Normal	No	No	Norway	5.1	[7]
c.337-338delGAinsTTT	p.Asp113Phefs*15	E3	Frameshift	20 M	Yes	NR	16y	Yes	NR	Star-shaped cataract 17y	No	Cerebellar atrophy	NR	No	NR	J-12	[8]
c.337-338delGAinsTTT	p.Asp113Phefs*15	E3	Frameshift	17 M	Yes	NR	10y	Yes	NR	Star-shaped cataract 10y	No	Cerebellar atrophy	NR	No	NR	J-13	[8]
c.337-338delGAinsTTT	p.Asp113Phefs*15	E3	Frameshift	36 F	NR	NR	12y	Yes	Rod-cone dystrophy	Posterior subcapsular cataract 32y	Yes	NR	NR	No	NR	E-7	[8]
c.337-338delGAinsTTT	p.Asp113Phefs*15	E3	Frameshift	32 F	Yes	NR	17y	Yes	Rod-cone dystrophy	Posterior subcapsular cataract 32y	45y	NR	NR	No	NR	B-2	[8]
c.337-338delGAinsTTT c.341dup	p.Asp113Phefs15 p.Leu114Phefs14	E3 E3	Frameshift Frameshift	39 M	NR	NR	33y	Yes	Rod-cone dystrophy	Star-shaped cataract 29y	NR	NR	NR	No	NR	L-15	[8]
c.337-338delGAinsTTT c.423-1_425del	p.Asp113Phefs*15 p.(?)	E3 I3	Frameshift Splice site	33 M	Yes	Subtle foot drop; absent Achilles tendon reflexes	No	Yes	NR	Sutural cataract 3y	27y	Normal	NR	No	NR	C-3	[8]
c.337-338delGAinsTTT c.423-1_425del	p.Asp113Phefs*15 p.(?)	E3 I3	Frameshift Splice site	33 M	Yes	Distal muscle weakness; sensory loss	Yes	Yes		Sutural cataract 3y	27y	Normal	NR	No	NR	C-4	[8]
c.337-338delGAinsTTT c.423-1_425del	p.Asp113Phefs*15 p.(?)	E3 I3	Frameshift Splice site	38 M	Yes	Abnormal gait pattern; distal sensory loss	20y	Yes		Star-shaped cataract 4y	31y	Cerebellar atrophy	NR	No	NR	C-5	[8]
c.337-338delGAinsTTT c.1075del	p.Asp113Phefs15 p.Val359Phefs27	E3 E12	Frameshift Frameshift	47 M	Yes	Pes cavus, hammertoes, distal sensory loss, absent tendon reflexes 8y	28y	Yes	Rod-cone dystrophy	36y	8y	Normal	NR	No	NR	A-1	[8]
c.374 C > T c.1154T > C	p.Thr125Met p.Leu385Pro	E3 E12	Missense Missense	53 M	NR	NR	44y progressive	Yes	NR	Posterior polar cataract 41y	NR	NR	NR	Epilepsy; learning difficulties	NR	ABHD12-5 I-11	(8, 34)
c.379-385del AACTACT ins GATTCCTTATAT ACCATTGTAGTC TTACTGCTTTTG GTGAACACA	p.Asn127Aspfs*23	E3	Deletion-Insertion	36 M	Demyelinating polyneuropathy	Yes	5y Deaf	No	NR	28y	15y ataxic walk	Normal	NR	No	France	XIX.1	[12]
c.447G > A c.557G > C	p.Trp159* p.Arg186Pro	E4 E5	Nonsense Missense	30 M	Yes	Distal sensory loss; reduced tendon reflexes	Yes	Yes	Rod-cone dystrophy	Cortical cataract	Wide-based gait; Stuttering speech; ataxic gait	Normal	No	No	Netherlands	W08-1833 D-6	(8, 40)
c.601dup	p.Val201Glyfs*4	E6	Frameshift	25 M	Yes	Pes cavus; slight gait disturbance	Yes	Yes	Abnormal	Yes	Yes	Cerebellar atrophy	No	No	Iran	IV.1	This study
c.601dup	p.Val201Glyfs*4	E6	Frameshift	18 F	Yes	Pes cavus	Yes	Yes	Abnormal	Yes	No	Normal	No	No	Iran	IV.2	This study
c.620–2 A > G		I6	Splice site	34 M	Yes	31y; Lower limb muscle weakness	20y progressive	Yes	Rod-cone dystrophy	26y	No	NR	NR	No	NR	ABHD12-4 G-9	(8, 34)
c.758 C > G	p.Thr253Arg	E8	Missense	31 F	Demyelinating polyneuropathy	Sensory loss	31y bilateral CI	Yes	NR	Posterior subcapsular cataract8y	ataxia 16y; mild intentional tremor; mild dysarthria; wheelchair-bound	Normal	NR	Decreased function of the labyrinths	Swedish	II.1	[38]
c.784 C > T c.867 + 5G > A	p.Arg262*	E8 I9	Nonsense Splice site	53 M	Yes	53y; Distal sensory loss	20y progressive	Yes	NR	No	No	NR	NR	No	NR	ABHD12-6 F-8	(8, 34)
c.784 C > T	p.Arg262*	E8	Nonsense	21 M	Demyelinating polyneuropathy	Pes cavus: reduced tendon reflexes at upper and lower limbs	9y 17y CI	No	NR	Yes	Stance ataxia	Cerebellar atrophy	No	No	Iraq	A	[35]
c.784 C > T	p.Arg262*	E8	Nonsense	25 M	Demyelinating polyneuropathy	Sensory loss; Loss of Achilles and patellar tendon reflexes	12y 18y CI	Yes	NR	Yes	Slight bilateral limb ataxia	NR	NR	No	Iraq	B	[35]
c.846-852dupTAAGAGC	p.His285fs*1	E9	Frameshift	11 M	Yes	Absent tendon reflexes; moderate muscle weakness at lower limbs	No	No	NR	No	3-4y; limb ataxia ; horizontal nystagmus; dysarthria; dysmetria delayed walking at 15 months; action and intention tremor	Cerebellar atrophy	Extensor planter response at lower limbs	No	Algeria	8.1	[7]
c.846-852dupTAAGAGC	p.His285fs*1	E9	Frameshift	10 F	Yes	Absent tendon reflexes at lower limbs	No	No	NR	No	4-5y; gait ataxia	Vermian atrophy	Extensor planter response at lower limbs	No	Algeria	8.2	[7]
c.846-852dupTAAGAGC	p.His285fs*1	E9	Frameshift	44 M	Demyelinating polyneuropathy	Pes cavus; sensory loss; absent tendon reflexes at lower limbs; scoliosis	Yes	Amblyopia	NR	NR	7-10y limb ataxia; dysarthria; dysmetria at upper limbs with adiadocokinesia; head titubation	Vermian atrophy	Extensor planter response at lower limbs; macroglossia	No	Algeria	9.1	[7]
c.846-852dupTAAGAGC	p.His285fs*1	E9	Frameshift	26 F	Demyelinating polyneuropathy	Pes cavus; sensory loss; reduced tendon reflexes at upper limbs, and absent at lower limbs; tongue fasciculation	Deaf	Yes	NR	Yes	4-9y gait and limb ataxia; horizontal nystagmus; moderate dysarthria; dysmetria at upper and lower limbs	Vermian atrophy	Extensor planter response at lower limbs;	No	Algeria	9.2	[7]
c.846-852dupTAAGAGC	p.His285fs*1	E9	Frameshift	26 F	Severe demyelinating polyneuropathy on nerve biopsy	Pes cavus; sensory loss; absent tendon reflexes	6y	No	NR	No	6-12y limb ataxia	Normal	Indifferent plantar response	No	Algeria	10.1	[7]
c.846-852dupTAAGAGC	p.His285fs*1	E9	Frameshift	19 F	Yes	12y; pes cavus; sensory loss; absent tendon reflexes at upper and lower limbs	NR	NR	NR	NR	No	NR	NR	No	Algeria	10.2	[7]
c.846-852dupTAAGAGC	p.His285fs*1	E9	Frameshift	32 F	Axonal polyneuropathy	Pes cavus; sensory loss; absent tendon reflexes at lower limbs	Yes	Decreased visual acuity and amblyopia	NR	No	16-20y; gait ataxia; dysarthria; dysmetria at upper limbs	Cerebellar atrophy	Extensor plantar response at lower limbs	No	Algeria	11.1	[7]
c.846-852dupTAAGAGC	p.His285fs*1	E9	Frameshift	23 F	Yes	NR	Yes	Yes	NR	Yes	Yes	NR	NR	No	Spain	10	[42]
c.1054 C > T	p.Arg352*	E12	Nonsense	50 F	Abnormal	34y; pes cavus; hammertoes;	17y	20y	NR	22y	18y; dysarthria; gait ataxia; jerky eye movement tremor in hand	Cerebellar atrophy Increased signal in periventricular white matter	Flexor planter response; spasticity;	No	USA	7.1	[7]
c.1054 C > T	p.Arg352*	E12	Nonsense	29 F	Demyelinating polyneuropathy	Pes cavus; sensory loss; absent tendon reflexes; a mild waddling	16y	Yes	NR	Yes	Gait ataxia; progressive jerky tremor; mild titubation of the trunk; mild proximal tetraparesis; dysmetria; mild bilateral ptosis; congenital convergent strabismus	Global moderate cerebral/cerebellar atrophy	NR	Mild learning disabilities	Portugal		[9]
c.1054 C > T c.1196del	p.Arg352* p.399Serfs122	E12 E13	Nonsense	48 F	NR	NR	No	yes	No Rod-cone dystrophy	Yes	No	NR	NR	No	NR	ABHD12-1	[34]
c.1063 C > T	p.Arg355*	E12	Nonsense	46 F	Yes	NR	Yes	Yes	Rod-cone dystrophy	Cerulean cataract	Yes	NR	NR		NR	K-14	[8]
c.1116 C > G	p.His372Gln	E12	Missense	38 F	Demyelinating polyneuropathy	Distal symmetric hypoesthesia to touch and pain; achilles reflex abolished	38y	Yes	Diminished	Yes	No	Cerebral and cerebellar atrophy	NR	No	Spain	RP-1487	[40]
c.1129 A > T 59 Kb deletion including exon 1	p.Lys377*	E12 E1	Nonsense Deletion	29 F	Demyelinating polyneuropathy	Pes cavus; sensory loss; absent tendon reflexes	HL from Childhood 21y bilateral CI	Yes	Abnormal	Yes	Steppage gait; mild dysmetria	Normal	Flexor plantar response	No	Japan	III.1	[11]

Abbreviations: AA, amino acid; E, exon; I, Intron; HL, hearing loss; RP, retinitis pigmentosa; ERG, electroretinography; MR, magnetic resonance; CT, computed tomography; Family case; the patients ID in relevant article; Ref, reference; M, male; F, female; Y, year; CI, cochlear implant; NR, not reported in article. * Nucleotide numbering is based on reference sequence NM_001042472.3.

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