Table 1 Summary of the genotype–phenotype correlation of chromosome Xq22.1–q22.3 deletions
Author | Age/Sex | Deletion regionsa and/or genes | Deletion size | Phenotype |
|---|---|---|---|---|
Pelizaeus–Merzbacher disease, PMD /Spastic paraplegia type 2, SPG2 (defects in PLP1 gene) | ||||
Raskind et al. [8] | 35 year/M | Complete deletion of PLP1 gene | 29 kb | Motor development delay, severe dysarthria and scanning speech, gross pendular horizontal nystagmus on lateral gaze to either side, cannot walk, optic disks pale, poorly coordinated dystonic movements of both arms, elbows contractures, both lower extremities spasticity, bilateral ankle clonus, bilateral toes grasping responses and right Bakinski reflex positive, jaw jerk 1 + , snout reflex positive |
17 year/M (His older half-brother) | In the postnatal period: seizure; at age 15 years: alert, little purposeful movement, moving eyebrows and shaking head to answer questions, neck and fingers hyperextended, elbows, wrists, hips, and knees flexion contractures | |||
4 year/M (His nephew) | Motor developmental delay, spastic diplegia, tendon reflexes hyperactive, bilateral extensor plantar responses, right optic nerve pallor, bilateral increased signal intensity in the periventricular white matter | |||
59 year/F (His mother) | Knee reflexes hyperactive, upward gaze restrict, smooth-pursuit eye movements coordinated poorly | |||
Inoue et al. [9] | 10 year/M | ChrX: 102,993,718–103,510,104 | 0.5 Mb | Motor development delay, spasticit particularly in lower extremities, dysmyelination, brainstem auditory evoked potentials abnormal |
30 year /F (His mother) | His mother: walking difficulty from third decade. Subsequently, spasticity and personality changes, mental deterioration, cerebral white matter changes | |||
10 year/M | ChrX: 102,957,289–103,314,254 | 0.4 Mb | At 18 months: unable to sit unsupported, roll over and no intelligible speech, spasticity; over the next few years: dysarthric; at age 5 years: the cerebrum delayed; at age 7 years: speech dysarthria and slowing, MRI revealed progressive abnormalities in cerebral white matter; at age 10 years: brainstem auditory and somatosensory evoked potentials were abnorma, loss of self-reliance, optic atrophy | |
32 year/F (His mother) | bilateral pes cavus deformities of the feet, increased deep tendon reflexes and muscle tone in the lower extremities, perform tandem gait losing | |||
Hübner et al. [10] | unknown | unknown, but complete deletion of PLP1 and RAB9L genes | 115 kb | PMD syndrome |
unknown/M (Affected brother) | After birth handicapped | |||
unknown | unknown, but complete deletion of PLP1 and RAB9L genes | 115 kb | PMD syndrome | |
unknown/M (Affected brother) | After birth handicapped | |||
Lee et al. [11] | unknown/M | ChrX: 103,009,829–103,214,881 | 190 kb | PMD syndrome |
Torisu et al. [12] | 2 year/M | ChrX: 103,018,951–103,092,038 | 73 kb | Spastic quadriplegia, mental retardation, microcephaly, brainstem auditory evoked potentials prolonged, hypomyelination, axonal involvement, nerve conduction velocity of the lower extremities decreased |
Matsufuji et al. [13] | 29 year/M | ChrX: 103,033,333–103,066,899 (Partial deletion of PLP1 gene) | 33 kb | Spastic quadriplegia, dysarthria, ataxia, dysphagia, intellectual delay |
59 year/F (His mother) | His mother has spastic diplegia, dementia | |||
31 year/F (His sister) | His sister has spastic diplegia, motor developmental delay, dysphagia from childhood | |||
Yamamoto et al. [14] | 6 year/F | ChrX: 101,365,862–105,847,036 | 4.4 Mb | Wide intermamillary distance, constipation, low-set ears, anterior hypopituitarism, large for gestational age, tall stature, blepharophimosis, high palate, narrow palate, prominent nasal bridge, wide nasal bridge, broad toe, hypotonia, joint laxity, macrocephaly, micrognathia, overlapping toe, short foot, abnormal CNS myelination, hydrocephalus, hypoplasia of the corpus callosum |
3 year/F | ChrX: 100,659,116–105,523,589 | 4.8 Mb | Developmental delay, hypersomnia, white matter hypoplasia, myelination delay, corpus callosum hypoplasia, ventriculomegaly. language skills lose, cannot sit or walk, triangular face, strabismus, jaw prominent, pesequinovarus, intellectual disability | |
16 year/F | ChrX: 100,907,884–103,982,269 | 3 Mb | Scoliosis, bilateral hearing loss, constipation, advanced bone age, aphasic, incontinent, hair growing slow, bifrontal narrowing, deep-set eyes, a prominent nasal bridge, full upper lip, a prominent jaw, deep palmer creases and prominent volar pads | |
1 year/F | ChrX: 101,982,865–102,233,526 | 0.25 Mb | Motor developmental delay, bilateral sensorineuronal deafness | |
7 year/F | ChrX: 102,959,459–103,044,544 (Partial deletion of PLP1 gene) | 85 kb | Early infancy: psychomotor developmental delay; at 18 months: cannot sit; at age 6 years: cannot walk, delayed myelination, aphasic, incontinent, pain perception impaired, sleeps poorly, strabismus, intellectual disability, leukodystrophy | |
Brender et al. [15] | 16 year/F | Deletion of NGFRAP1, TCEAL1, MORFL2, PLP1, RAB9B, and H2BFWT genes | 712 kb | At birth: nystagmus; at 6 months: delayed motor development, spasticity; at age 3 years: aphasia; at 14 year: loss of expression, nystagmus, exotropia, agitation; at 7 years: cannot walking; at ages of 4, 9, 13, and 17: the frontal horn to the occipital horn of the lateral ventricles bilaterally linear increased; at 16 years: onset seizure disorder, Electroencephalogram demonstrated abundant bursts of generalized spike, polyspike, and slow wave activity; at 17 years: remained nonverbal |
Kinoshita et al. [16] | 3 year/F | Del(X)(q22.1q22.2) / Deletion of 39 genes, including PLP1 gene | 2.26 Mb | Incomplete lung formation, feeding difficulty, hydration, milestones delayed, communicate, recognize and identify lose, cannot walk, emotions lose, broad forehead, small pointed nose, left eye strabismus, thin upper lip, dental decay, grasping difficult, arms and legs strength strength |
Hijazi et al. [17] | 13 year/F | ChrX: 100,866,604–103,411,980 | 2.5 Mb | Strabismus, posterior white matter signal, hypotonia followed by spasticity, gastroesophageal reflux disease, poor weight gain, constipation |
9 year/F | ChrX: 102,615,641–103,309,503 | 693 kb | Strabismus, nystagmus, delayed myelination, thin corpus callosum, cerebral atrophy, hypotonia mixed with spasticity, gastroesophageal reflux disease, facial dysmorphic features | |
3.5 year/F | ChrX: 101029649-106702784 | 5.6 Mb | Strabismus, delayed myelination in parietal/periventricular regions, hypotonia followed by dystonia, gastroesophageal reflux disease, abnormal brain auditory evoked potential, dysmorphic features | |
8 year/F | ChrX: 102,066,350–105,409,822 | 3.3 Mb | Strabismus, left amblyopia, diffuse hypomyelination, partially progressed myelination, thincorpus callosum, white matter atrophy, hypotonia then spasticity, gastroesophageal reflux disease, constipation, Seizure, ventricular septal defect, decreased bone mineral density, hypothyroidism | |
unknown/F | ChrX: 102,436,725–105,520,605 | 3.0 Mb | Unknown | |
15 year/M | ChrX: 103,029,773–103,036,548 | 6.7 kb | Strabismus, diffuse hypomyelination, thin corpus callosum, brain atrophy, spasticity, dystonia, Seizure, extended latency in brain auditory evoked potential, peripheral neuropathy | |
16 year/M | ChrX: 102,967,297–103,038,606 | 71 kb | Strabismus, periventricular white matter change, hypotonia, spasticity, gastroesophageal reflux disease, poor weight gain, abnormal electroencephalogram, initially diagnosed as cerebral palsy with Periventricular leukomalacia | |
unknown/M | ChrX: 102,543,473–103,398,234 | 854 kb | Unknown | |
X-linked agammaglobulinaemia, XLA/Mohr–Tranebjaerg syndrome, MTS (defects in BTK/DDP1/TIMM8A gene)b | ||||
Jin et al. [18] | 9 year/M | Partial deletion of BTK gene andcomplete deletion of deafness/ dystonia peptide (DDP) gene | 21 kb | At 12 months: deafness, dystonia, mental deficiency, recurrent infections; at age 2 years: sensorineural deafness; at age 5 years: dystonia |
Richter et al. [19] | 6 year/M | Partial deletion of BTK gene andcomplete deletion of DDP gene | 19 kb | At 10 months: pseudomonas aeruginosa sepsis, severe oral aphthous, cutaneousnecrotic lesions, leukopenia andneutropenia, XLA; at age 3–4 years: language skills not developing |
9 year/M | Partial deletion of BTK gene andcomplete deletion of DDP gene | 4.2 kb | At 8 months: profound neutropenia, low levels of serum immunoglobulins, XLA; at age 3–4 years: speech definitely stop developing | |
14 year/M | Partial deletion of BTK gene andcomplete deletion of DDP gene | 7 kb | At 18 months: otitis, conjunctivitis, upper and lower respiratory tract infections; at 30 months: P. aeruginosa sepsis, necrotic skin lesions, neutropenia, profound hypogammaglobulinemia, B cells absence, XLA, speech delayed, hearing loss, emotional instability, attention deficit disorder, learning disabilities, auditory and visual processing defects | |
Pizzuti et al. [20] | 24 year/M | Partial deletion of BTK gene andcomplete deletion of DDP gene | unknown | At age 2 years: bilateral hearing loss, recurrent infections, bruton agammaglobulinemia; at age 15 years: visual lose; at age 19 years: writing difficulties, visual acuity, hearing impaired, the right upper limb dystonic posturing, intellectual deficit |
Sedivá et al. [21] | 33 year/M | Deletion includes the last exon of the BTK gene and both exons of the TIMM8A gene | 30 kb | Deafness, abnormal speech, aggressive behavior, muscle wasting |
25 year/M (Brother of 33 year old man) | Respiratory infections, progressive deafness | |||
6 year/M | Deletion includes the exons 6–19 of the BTK gene and both exons of the TIMM8A gene | 22 kb | At 3 months: respiratory infections; at 7 months, XLA, psychomotor retardation, speech impairment; at age 4 years: sensorineural hearing loss | |
5 year/ M (Brother of 6 year oldboy) | At 2 months: XLA; at 7 months: acute bronchopneumonia; since 16 months: chronic bronchitis; at age 2.5 years: speech development delayed | |||
13 year/M | Deletion of BTK, TIMM8A, TAF7L, and DRP2 genes | 196 kb | At 6 months: respiratory distress, pneumonia, neutropenia; at 8 months: XLA, pneumonia; at age 3 years: language and motor development delay, hearing loss | |
6 year/M (died) | Deletion includes the last exon of the BTK gene and the entire TIMM8A gene | 20 kb | At age 6 years: progressive dystonia, neurological impairment, general wasting, died | |
Jyonouchi et al. [22] | 6 year/M | ChrX: 100,288,859–100,453,630 | 155 kb | At 5–6 months: bacterial pneumonia, agammaglobulinemia; at age 2–3 years: speech delay, furuncles on trunk and extremities, dental caries, malnourished, hearing loss, speech delay, sinopulmonary infection, circulating CD19 + B cells absence, IgA, IgM, and IgE undetectable |
6 year/M (Two identical twins) | ||||
Brookes et al. [23] | 28 year/M | Deletion included exons 17–19 of BTK and exon 1 of DDP1/TIMM8a genes | 6 kb | At 4 months: acute otitis media; at age 1 years: otitis media, recurrent sinusitis, viral upper respiratory tract infections, cutaneous staphylococcus infection, neutropenia, panhypoglobulinemia; at age 5 years: XLA, B lymphocytes lack, communication limited, receptive and expressive language delay, sensorineural hearing loss, speech and language delay persisted |
Arai et al. [24] | 15 year/M | Deletion included exons 16–19 of BTK and TIMM8a genes | 63 kb | At age 1 years: deafness; at age 7 years: XLA |
10 year/M | Deletion included exons 6–19 of BTK and TIMM8a, TAF7L, DRP2 genes | 149.7 kb | At 12 months: otitis media, sinusitis; at 18 months: deafness, autism; at age 8 years: agammaglobulinemia, lack of circulating B cells, XLA, hearing losses | |
Shaker et al. [25] | 27 year/M | Deletion of BTK, TIMM8A, and TAF7L genes | 111 kb | At 11 months: XLA, acute-onset bilateral flaccid paralysis, lower extremities sensory loss, loss of reflexes, pain, and temperature below the T10 level, low levels of immunoglobulins, B-cells absent, spastic lower extremity paraplegia; at age 2 years: hearing loss; at age 20 years: metastatic testicular seminoma |
Szaflarska et al. [26] | 6 months/M | ChrX: 100,601,727–100,617,576 | 16 kb | At 5 months: skin abscesses; at 6 months: generalised purulent skin infection, fever and eutropenia; at 7 months: pneumonia, low concentrations of serum immunoglobulins, absolute number of T cells elevated, B lymphocytes absent |
Other syndromes | ||||
Grillo et al. [27] | 7 year/F | ChrX: 100,934,364–102,047,069 | 1.1 Mb | At birth: asphyxia, cleft palate surgically; at 18 months: deambulation and speech absent; at age 3 years: sleep tremors; at age 4 years: microbrachycephaly, muscle hypotonia, an unspecific periventricular white matter alteration at cerebral; at age 7 years: mental retardation, hypertricosis on upper limbs, distal muscle hypotrophy of lower limbs, scoliosis and facial ysmorphisms suchascoarse face, small forehead, thick lips, smooth philtrum and low set ears, autistic spectrum disorder, stereotypic movements, self-mutilation |
42 year/F (His mother) | 1.1 Mb | Mental retardation, short stature, brachycephaly, epilepsy, a borderline personality disorder | ||
Shimojima et al. [28] | 12 year/M | ChrX: 105,167,104–106,028,458 | 862 kb | At birth: overweight, scant scalp hair, forehead prominent, cleft lip and palate, psychomotor development, hypotonia, episodes of febrile seizures; at age 4 years: scoliosis, orthostatic hypotension; at 6 years: right eye cataract, retinal detachment, highly arched eyebrows, epicanthus, left internal strabismus, flat nose, post-operative cleft lip, thin extremities, generalized hypotonia, extremities hyporeflexia, joints hypermobility. generalized skin hyperextensibility, hair growth slow, speak loss |
Labonne et al. [29] | 11 year/F | ChrX: 102,882,657-102,987,229 | 105 kb | At 8 weeks: manifesting nystagmus; at 8 months: cannot sitting or weight bearing; at 9 months: gross motor skills delayed; at 15 months: develop movement patterns, slow; at 20 months: developmental delay, cannot crawling; at 2 years and 1 month: generalized tonic clonic seizure, fever; at 2 years and 3 months: cannot loading; at 2 years and 8 months: development delayed, walked with a wide spaced ataxic gait, hand movements displayed, stare and look blankly; at 3 years and 4 months: deep blue, lightly pigmented irides, displayed frontal bossing, a flat occiput, prominent chin, fifth finger clinodactyly; at 4 years and 1 month: sleep patterns disturbed; at 4 years and 7 months: global developmental delay, hypermetropic astigmatism, minor jerky eye movement; at 5 years: learning difficulties, intermittent episodes of distress, glycosuria, stereotypic movements, walk in a side-to-side stepping, poor coordination, cannot speech, heart murmur, constipation, eating nonfood, cannot independent; at age 6 years: chicken pox; at age 7 years: abdominal discomfort |
Cao et al. [30] | 8 week/M | ChrX: 100,857,290–101,991,488 | 1.1 Mb | Thrive failure, hypoglycemia, subtle dysmorphic features, umbilical hernia, hypotonia with spasticity in the lower extremities, focal enlargement of frontal temporal lobe, respiratory failure with thoracic insufficiency syndrome, tracheomalacia, and laryngomalacia |
Shirai et al. [31] | 17 month/ M | ChrX: 101,381,936–102,754,792 | 1.4 Mb | After birth: respiratory failure, suspected laryngomalacia and laryngeal wheezing, dysphagia, congenital nasolacrimal duct cyst; at 9 months: tonic seizures, distinctive facial features, including mid-face hypoplasia, micrognathia, redundant nuchal skin, extremities hypertonus, cerebral volume reduced, cannot control head, roll over or make eye contact lose, psychomotor developmental delay, bedridden |
Normal phenotype with Xq22.1–q22.3 deletions | ||||
Vaglio et al. [32] | 4 year/F | Deletion of a terminal Xq spanning Xq22.1→qter | unknown | Normal |
This study | 1 month/F | ChrX: 100,460,000–105,740,000 | 5.28 Mb | Normal |
12 year/F | Normal | |||
37 year/F | Normal | |||
65 year/F | Normal | |||