A Novel Missense Mutation in TWNK Gene Causing Perrault Syndrome Type 5 in a Chinese Family and Review of the Literature

Figures & data

Figure 1 Pedigree and sequence analysis of the Chinese family. (A) Pedigree of the Chinese family. The filled circle indicates affected individual, and the open circle and box indicate non-affected individuals. The proband is indicated by an arrow. (B) Sanger sequencing confirmation of the Chinese family. The proband (II-1) carried compound heterozygous mutations: c.1172G>A inherited from his father (I-1) and c.1752C>A from his mother (I-2). Square: Male; Circle: Female.

Figure 2 Scheme of Twinkle structure (NP_068602) and distribution of pathogenic variants associated with Perrault syndrome. The N-terminal contains the mitochondrial targeting sequence (MTS); then, there is an N-terminal primase domain, a C-terminal helicase domain, and a linker region connecting the two domains. The novel missense variant identified in the proband in this study is in red.

Table 1 Common Clinical Features of Patients with TWNK Mutations in PRLTS5

Organ System	Clinical Features	Our Case	Summary
	Gender	F	F/M=18:2
	Diagnosed age	11 years	6–58 years
	Karyotype	46, XX^a	10/20 (50%)^a
Ears	SNLH	Yes	20/20 (100%)
Endocrine	Ovarian dysfunction	Yes	17/20 (85%)
	Lack of secondary sexual characteristics	NA	3/20 (15%)
	Hypergonadotropinemia	Yes	7/20 (35%)
	Primary amenorrhea	Yes	14/20 (70%)
	POI	No	2/20 (10%)
	Gonadal dysgenesis	Small ovaries and uterus	6/20 (30%)
	Thyroid dysfunction	No	4/20 (20%)
Peripheral Nervous System	Peripheral neuropathy	Yes	18/20 (90%)
	Electrophysiology abnormalities	NA	14/20 (70%)
	Deep tendon reflex of UL	Absent	12/20 (60%)
	Deep tendon reflex of LL	Absent	15/20 (75%)
Central Nervous System	Brain/cervical spine MRI abnormalities	NA	13/20 (65%)
	Ataxia	Yes	20/20 (100%)
	Romberg’s sign	Positive	11/20 (55%)
Musculoskeletal	Muscle weakness	No	4/20 (20%)
	Muscle atrophy	No	6/20 (30%)
	Motor dysfunction	No	7/20 (35%)
	Pes cavus	NA	10/20 (50%)
	High-arched palate	Yes	5/20 (25%)
Eyes	Nystagmus	Yes	14/20 (70%)
	Ophthalmoplegia	NA	6/20 (30%)
Development	Intellectual disability	No	3/20 (15%)
	Dysarthria	No	9/20 (45%)

Notes: ^a10 out of 20 patients were tested for karyotype, these 10 patients were all females and the karyotypes were all 46XX. The other 10 patients including 2 males had no karyotype data. More detailed information see Table S1.

Abbreviations: F, female; M, male; NA, not available; SNHL, sensory neural hearing loss; POI, primary ovarian insufficiency; UL, upper limbs; LL, lower limbs.

Table 2 Reported TWNK Mutations in PRLTS5

Family	Orgin	Nucleotide Changes	Amino Acid Changes	Reference
I	Japanese	c.[1172G>A; 1754A>G]	p.[Arg391His; Asn585Ser]	[^Citation2]
II	American with European ancestry	c.[1321T>G; 1519G>A]	p.[Trp441Gly; Val507Ile]	[^Citation2]
III	Morocco	c.793C>T HMZ	p.Arg265Cys	[^Citation3]
IV	Norwegian	c.[968G>A; 1196A>G]	p.[Arg323Gln; Asn399Ser]	[^Citation5]
V	Polish	c.[1196A>G; 1802G>A]	p.[Asn399Ser; Arg601Gln]	[^Citation26]
VI	Spanish	c.[85C>T; 1886C>T]	p.[Arg29*; Ser629Phe]	[^Citation4]
VII	Chinese	c.[794G>A; 1181G>A]	p.[Arg265His; Arg394His]	[^Citation27]
VIII	Hungarian	c.[1196A>G;1358G>A]	p.[Asn399Ser;Arg453Gln]	[^Citation14]
IX	Italian	c.[743T>C; 1519G>A]	p.[Phe248Ser; Val507Ile]	[^Citation28]
X	Chinese	c.[1172G>A; 1844G>C]	p.[Arg391His; Gly615Ala]	[^Citation13]
XI	Japanese	c.1358G>A HMZ	p.Arg453Gln	[^Citation12]
XII	Chinese	c.[1172G>A; 1752C>A]	p.[Arg391His;Asp584Glu]	Our case

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