Table 1 Previous published reports of Noonan syndrome and LZTR1 variants
From: LZTR1 molecular genetic overlap with clinical implications for Noonan syndrome and schwannomatosis
Variant(s) | Zygosity | Mode of inheritance | Clinical diagnosis/Features | PMID |
|---|---|---|---|---|
c.742G>A (p.Gly248Arg) | Heterozygous | Maternal | Proband: typical facial features, short/webbed neck, pectus deformity, pulmonary valve stenosis/atrial septal defect, ophthalmological abnormality (prominent corneal nerves), lacrimal duct obstruction Mother: typical facial features, short/webbed neck, pectus deformity, mitral valve prolapse, height -2.5 SDS Grandfather: typical facial features, short/webbed neck, pectus deformity, mitral valve prolapse, abnormal hemostasis (Factor XI deficiency), height -2.9 SDS | 25795793 |
c.850C>T (p.Arg284Cys) | Heterozygous | Maternal | Proband: typical facial features, abnormal hemostasis (prolonged ATTP) Mother: typical facial features, nevi Sibling 1: typical facial features, ectodermal findings (curly hair, sparse eyebrows, hyperkeratosis pilaris), nevi Sibling 2: typical facial features, short/webbed neck, ectodermal findings (curly hair), hemangioma Half Sibling 1: typical facial features Half Sibling 2: typical facial features, height -3.8 SDS | 25795793 |
c.859C>T (p.His287Tyr) | Heterozygous | De novo | Proband: typical facial features, pulmonary valve stenosis/atrial septal defect, cryptorchidism, abnormal hemostasis (prolonged ATTP), ophthalmological abnormality (prominent corneal nerves), developmental delay, learning disability | 25795793 |
c.356A>G (p.Tyr119Cys) | Heterozygous | De novo | Proband: typical facial features, left ventricular hypertrophy, lymphedema, varicose veins | 25795793 |
c.740C>A (p.Ser247Asn) | Heterozygous | Maternal | Proband: typical facial features, short/webbed neck, pectus deformity, mitral valve insufficiency, ectodermal findings (curly hair), developmental delay, learning disability, Mother: typical facial features, short/webbed neck, aorta coarctation, hyperopia, tumors (neurinomas of right hand and forearm, lipoma of thorax = schwannomas) | 25795793 |
c.881G>T (p.Arg294Leu)/ c.2212C>T (p.Gln738*) | Compound heterozygous | Maternal/paternal | Proband: typical NS facial features, pectus excavatum, short stature treated with growth hormone, growth hormone deficiency, thickening of the left side of the optic chiasm suggestive of glioma, Senning correction surgery for transposition of the great vessels, pulmonary stenosis, interventricular and interatrial communication | 29959388 |
c.509G>C (p.Arg170Pro)/ c.2374T>G (p.Cys792Gly) | Compound heterozygous | Maternal/paternal Autosomal recessive | Proband: NS clinical phenotype, short stature, left ventricular outflow tract obstruction, atrial septal defect | 30732632 |
c.850C>T (p.Arg284Cys) | Heterozygous | Maternal Dominant | Proband: Typical NS dysmorphism, Charcot-Marie-Tooth syndrome, manual dyspraxia and distal muscular weakness, short statue treated with growth hormone, scoliosis and lumbar scoliosis, partial complex seizures leading to identification of a right fronto-temporo-insular tumor, severe kyphoscoliosis with a gibbus, pectus excavatum, generalized amyotrophy, mild defect in factor XI, grade IV gliomablastoma | 30664951 |
c.1149+1G>T | Heterozygous | Maternal Autosomal dominant | Proband: typical NS appearance, short stature, delayed psychomotor development, frequent premature ventricular beats, hemivertebra deformity, scoliosis, refractive errors, growth hormone deficiency, pectus excavatum, café au lait spots, mild hypertrichosis Sibling: typical NS appearance, pectus carinatum, short stature Mother: mild typical NS appearance | 33407364 |
c.1084C>T (p.Arg362*)/ c.1149+1G>T | Compound heterozygous | Maternal/paternal Autosomal recessive | Proband: severe hypertrophic cardiomyopathy, mild pulmonary valve stenosis, characteristic NS facies, broad QRS complexes, right bundle branch block, left axis deviation, striking negative pattern in the left precordial leads | 31182298 |
c.2070-2A>G/ c.1735G>A (p.Val579Met) | Compound heterozygous | Paternal/maternal Autosomal recessive | Proband: severe hypertrophic cardiomyopathy without obstruction, left axis deviation, negative pattern in the left precordial leads, severe feeding problems | 31182298 |
c.355T>C (p.Tyr119His) | Not provided | De novo | Proband: typical craniofacial dysmorphology, pulmonary valve stenosis/branch pulmonary arterystenosis, slight asymmetric hypertrophy of inteventricular sept, café au lait spots, nevi or lentigines, permanence of fetal finger and toepads, narrow palate | 32514133 |
c.1430C > T (p.Ala477Val)/ three LRP1 variants | Heterozygous | Paternal/maternal | Proband: delayed development, height -4.98 SD, typical craniofacial dysmorphology, broad thorax with wide-spaced nipples, cubitus valgus, clinobrachydactyly, cryptorchidism, GH deficiency, previous epilepsy (rolandic type, absences), thoracolumbar scoliosis, generalized hirsutism | 32514133 |
c.347C > T (p.Ala116Val) | Heterozygous | De novo | Proband: typical facial dysmorphism, height -4.3 SD, short webbed neck with low posterior hairline, pectus deformity, heart murmur, hypertrophic cardiomyopathy, cryptorchidism, ostium secundum atrial septal defect, mitral anomaly, ectodermal findings, sparse eyebrows, ulerythema ophriogenes, developmental delay | |
c.628C > T (p.Arg210*)/c.2220-17C>A (p.Tyr741Hisfs*89) | Compound heterozygous | Paternal/maternal Autosomal recessive | Sibling 1: typical facial dysmorphism, broad/short neck, low posterior hairline, pectus carinatum or excavatum, congenital heart defect or valvular disease Sibling 2: prenatal hydrops, nuchal transl or cardiac findings, typical facial dysmorphism, broad/short neck, low posterior hairline, pectus carinatum or excavatum, congenital heart defect or valvular disease, curly hair, developmental delay Sibling 3: typical facial dysmorphism, broad/short neck, low posterior hairline, pectus carinatum or excavatum, wide-spaced nipples/broad chest, leukemia Sibling 4: prenatal hydrops, nuchal transl or cardiac findings, typical facial dysmorphism, broad/short neck, low posterior hairline, pectus carinatum or excavatum, wide-spaced nipples/broad chest, congenital heart defect or valvular disease, height < 3rd centile Several individuals in this family had suggestive schwannomas | 29469822 |
c.2178C>A (p.Tyr726*)/ c.1943-256C > T | Heterozygous | Paternal/maternal Autosomal recessive | Sibling 1: prenatal hydrops, nuchal transl or cardiac findings, typical facial dysmorphism, broad/short neck, low posterior hairline, wide-spaced nipples/broad chest, pectus carinatum or excavatum, cardiomyopathy, congenital heart defect or valvular disease, cryptorchidism, developmental delay/intellectual disability, height < 3rd centile Sibling 2: prenatal hydrops, nuchal transl or cardiac findings, typical facial dysmorphism, broad/short neck, cardiomyopathy, congenital heart defect or valvular disease, developmental delay/intellectual disability, height 3rd centile | 29469822 |
c.1943-256C > T; *70G>A/ c.1943-256C > T; *70G>A | Homozygous | Paternal/maternal Autosomal recessive | Sibling 1: prenatal hydrops, nuchal transl or cardiac findings, depressed or wide bridge, low set ears, broad/short neck, low posterior hairline, wide-spaced nipples/broad chest, cardiomyopathy, height < 3rd centile Sibling 2: prenatal hydrops, nuchal transl or cardiac findings, ptosis, downslanted palpebral fissures, low set ears, cardiomyopathy, congenital heart defect or valvular disease, height < 5-10th centile | 29469822 |
c.1687G>C (p.Glu563Gln) | Homozygous | Paternal/maternal Autosomal recessive | Sibling 1: typical facial dysmorphism, broad/short neck, low posterior hairline, pectus carinatum or excavatum, cardiomyopathy, congenital heart defect or valvular disease, developmental delay/intellectual disability Sibling 2: prenatal hydrops, nuchal transl or cardiac findings, broad/short neck, cardiomyopathy, congenital heart defect or valvular disease, cryptorchidism | 29469822 |
c.2407-2A>G/ c.2090G>A (p.Arg697Gln) | Compound heterozygous | Paternal/maternal Autosomal recessive | Sibling 1: prenatal hydrops, nuchal transl or cardiac findings, typical facial dysmorphism, broad/short neck, wide-spaced nipples/broad chest, curly hair, cardiomyopathy, congenital heart defect or valvular disease, height 3rd centile Sibling 2 (twins): prenatal hydrops, nuchal transl or cardiac findings, broad/short neck, wide-spaced nipples/broad chest, congenital heart defect or valvular disease | 29469822 |
c.27delG (p.Gln10fs*15)/ c.1149+1G>A | Compound heterozygous | Paternal/maternal Autosomal recessive | Proband: typical facial dysmorphism, broad/short neck, wide-spaced nipples/broad chest, height < 5th centile | 29469822 |
c.361C > G (p.His121Asp)/ c.2264G>A (p.Arg755Gln) | Compound heterozygous | Paternal/maternal Autosomal recessive | Proband: prenatal hydrops, nuchal transl or cardiac findings, typical facial dysmorphism, broad/short neck, low posterior hairline, wide-spaced nipples/broad chest, pectus carinatum or excavatum, curly hair, cardiomyopathy, congenital heart defect or valvular disease, developmental delay/intellectual disability, height < 3rd centile | 29469822 |
c.508C > T (p.Arg170Trp); c.614T>C (p.Ile205Thr)/ c.508C > T (p.Arg170Trp); c.614T>C (p.Ile205Thr) | Compound homozygous | Paternal/maternal Autosomal recessive | Proband: typical facial dysmorphism, broad/short neck, curly hair, cardiomyopathy, congenital heart defect or valvular disease, cryptorchidism developmental delay/intellectual disability, height < 3rd centile | 29469822 |
c.650A > C (p.Glu217Ala)/ c.650A > C (p.Glu217Ala) | Homozygous | Paternal/maternal Autosomal recessive | Proband: typical facial dysmorphism, broad/short neck, cardiomyopathy, congenital heart defect or valvular disease, developmental delay/intellectual disability, height 3rd centile | 29469822 |
c.2062C > G (p.Arg688Gly)/ c.1943-256C > T | Heterozygous | Paternal/maternal Autosomal recessive | Sibling 1: prenatal hydrops, nuchal transl or cardiac findings, typical facial dysmorphism, broad/short neck, wide-spaced nipples/broad chest, cardiomyopathy, developmental delay/intellectual disability, height < 3rd centile | 29469822 |
c.2325+1G>A/ c.1943-256C > T | Not provided | Paternal/maternal Autosomal recessive | Sibling 1: prenatal hydrops, nuchal transl or cardiac findings, typical facial dysmorphism, broad/short neck, wide-spaced nipples/broad chest, pectus carinatum or excavatum, cardiomyopathy, congenital heart defect or valvular disease | 29469822 |
c.2462T>C (p.Ile821Thr)/ c.2462T>C (p.Ile821Thr) | Homozygous | Paternal/maternal Autosomal recessive | Sibling 1: typical facial dysmorphism, low posterior hairline, wide-spaced nipples/broad chest, pectus carinatum or excavatum, curly hair, cardiomyopathy, congenital heart defect or valvular disease, developmental delay/intellectual disability Sibling 2: low set ears, post angulated ears, midface retrusion, low posterior hairline, wide-spaced nipples/broad chest, pectus carinatum or excavatum, cardiomyopathy, congenital heart defect or valvular disease, developmental delay/intellectual disability, height < 3rd centile | 29469822 |
c.406T>C (p.Tyr136His) | Heterozygous | De novo Autosomal dominant | Proband: abnormalities of the abdomen, atrioventrical valves, heart values and spatial orientation of the cardiac segments, coarctation of the aorta, heptamegaly, large for gestational age, malrotation of small bowel, malformation of the heart and great vessels, height 2-9th centile, mild typical facial dysmorphism | 30859559 |
c.434A > T (p.Asn145Ile) | Heterozygous | Maternal Autosomal dominant | Proband: short stature, characteristic NS facial features, mild pulmonary stenosis, mild learning difficulties, mild right bundle branch block with mild left ventricular dilation with a normal pulmonary valve, low posterior hairline, widely spaced nipples, mild pectus excavatum, café-au-lait macule, platelet dysfunction disorder Mother: mild clotting disorder, type 1 von Willebrand’s disease, mild learning difficulties, mild NS-like facial features Cousin: Cerebral Palsy, characteristic NS facial features, periventricular leukomalacia, global developmental delay, abnormal gait with increased limb tone, moderate learning difficulties, behavioural issues within the autistic spectrum disorders Aunt: childhood growth delay, delayed puberty, hypothyroidism, underweight Half Aunt: heart murmur, mitral valve prolapse, small spina bifida, subtle facial features of NS | 30859559 |
c.290G > T (p.Arg97Leu) | Not provided | De novo Autosomal dominant | Proband: prenatal cardiac findings (absent ductus venosus), atrial septal defect, typical NS facial features, downslanted palpebral fissures, epicanthus, wide spaced nipples/broad chest, curly hair hypertrophic cardiomyopathy, short stature, ventricular septal defect, foot abnormalities, delayed walking, scoliosis, impaired clotting, respiratory problems | 30859559 |
c.407A>G (p.Tyr136Cys) | Not provided | De novo Autosomal dominant | Proband: 2–3 toe syndactyly, typical NS facial features, barrel-shaped chest, cryptorchidism, delayed speech and language development, depressed nasal bridge, wide spaced nipples/broad chest, curly hair, generalised hypotonia, low-set posteriorly rotated ears, motor delay, unilateral ptosis, wide intermammillary distance, GH deficiency, mild pulmonary valve stenosis, short stature | 30859559 |
c.731C > G (p.Ser244Cys) | Not provided | De novo Autosomal dominant | Proband: café-au-lait spots, hypermetropia, typical NS facial features, low-set posteriorly rotated ears, wide spaced nipples/broad chest, pectus carinatum, webbed neck, short stature, single transverse palmar crease, strabismus, webbed neck | 30859559 |
c.742G>A (p.Gly248Arg) | Not provided | De novo Autosomal dominant | Proband: prenatal hydrops, depressed nasal bridge, epicanthus, microcephaly, preauricular pit, prominent metopic ridge, severe global developmental delay, perintal asphyxia, seizures, underweight, height 1st centile, marked micrognathia and feeding problems, facial features now atypical for NS, cubitus valgus, pectus excavatum, renal abnormalities, valvular heart disease | 30859559 |
c.1591G>A (p.Asp531Asn)/ c.628C > T (p.Arg210*) | Compound heterozygous | Autosomal recessive | Proband: autistic behaviour, global developmental delay, hypertrophic cardiomyopathy, long palpebral fissure, mitral valve prolapse, pes plantus, prominent fingertip pads, tonic–clonic seizures, facial features suggestive of Kabuki syndrome, height 3rd centile, cryptorchidism | 30859559 |
c.1149+1G > T/ c.2062C > T (p.Arg688Cys) | Compound heterozygous | Autosomal recessive | Proband: Bilateral ptosis, typical NS facial features, blue irides, downslanted palpebral fissures, hyperacusis, hypertelorism, joint hypermobility, square thumb, low-set posteriorly rotated ears, pectus carinatum, broad/short neck, wide spaced nipples/broad chest, proportionate short stature, mild developmental delay, delayed speech and language development | 30859559 |
c.628C > T (p.Arg210*)/ c.1735G>A (p.Val579Met) | Compound heterozygous | Autosomal recessive | Proband: rare biallelic variants in NEB lead to a “blended” phenotype, nuchal translucency abnormalities, typical NS facial features, blifid uvula, bilaterial ptosis, downslanted palpebral fissures, generalised joint laxity, hearing impairment, high palate, hypertelorism, long face, macrodontia, myopathy, pectus excavatum, pointed chin, renal duplication, retrognathia, mitral valve regurgitation, duplex kidney, mild developmental delay, delayed speech and language development, delayed walking, hypertonia, feeding problems, easy bruising | 30859559 |
c.1311G>A (p.Trp437*)/ c.-38T>A | Compound heterozygous | Suspected autosomal recessive | Proband: typical NS facial features, prenatal hydrops, nuchal translucency abnormalities, broad/short neck, webbed neck, low posterior hairline, wide spaced nipples/broad chest, left ventricle hypertrophy, foot abnormalities, delayed walking, hypotonia, joint laxity/ hypermobility Sibling: affected, died at birth | 30859559 |
c.1407G>A (p.Trp469*)/ c.2246A>G (p.Tyr749Cys) | Compound heterozygous | Suspected autosomal recessive | Proband: typical NS facial features, severe hypertrophic cardiomyopathy, broad/short neck, webbed neck, low posterior hairline, wide spaced nipples/broad chest, pes planus, mild developmental delay, impaired vision | 30859559 |
c.1382C>A (p.Ala461Asp)/ c.1385T>C (p.Ile462Thr) | Compound heterozygous | Maternal/paternal Suspected autosomal recessive | Proband: typical NS facial features, prenatal cardiomyopathy, broad/short neck, webbed neck, low posterior hairline, cubitus valgus, curly hair, cardiac hypertrophy, pulmonic stenosis, moderate developmental delay, delayed speech and language development | 30859559 |
c.848G> A (p.Arg283Gln) | Heterozygous | De novo | Proband: dysmorphic features, short stature, short neck, webbed neck, scoliosis, hyperelastic skin, hyperkeratosis, wrinkled palms and soles, café au lait spots, atrial septal defect, ventricular septal defect, pulmonary stenosis, patent ductus arteriosus, severe intellectual disability | 30368668 |
c.742G>A (p.Gly248Arg) | Heterozygous | Maternal Suspected autosomal dominant | Proband: Noonan-like syndrome, nuchal translucency, hypertelorism, ptosis, low-set ears, highly arched palate, anomalous origin of coronary artery, concealed penis Mother: ventricular septal defect, mild hypertelorism, downslanting palpebral fissures | 30368668 |
c.2102C>A (p.Pro701His)/ c.2069+2T>C | Compound heterozygous | Paternal/maternal Suspected autosomal recessive | Proband: hypertelorism, low-set ears, sparse eyebrows, short stature, short neck, scoliosis, pectus excavatum, hyperpigmentation, hypertropic cardiomyopathy, mild intellectual disability, squint, amblyopia, 5th brachymetapody | 30368668 |
c.428A>G (p.Asn143Ser) | Heterozygous | Paternal | Proband: relative macrocephaly, typical NS facial features, short stature, pectus carinatum, hyperkeratosis, wrinkled palms and soles, hyperpigmentation, naevus, hypertropic cardiomyopathy, cryptorchidism, intellectual disability, puffy palms | 30368668 |
c.606_650del (p.Met202fs) | Heterozygous | Paternal | Proband: pleural effusion, relative macrocephaly, typical NS facial features, short stature, short neck, webbing of neck, hypertropic cardiomyopathy, atrial septal defect, pulmonary stenosis, arrhythmia | 30368668 |
c.756_758del (p.Asn253del) | Heterozygous | De novo | Proband: relative macrocephaly, typical NS facial features, short stature, short neck, webbing of neck, cubitus valgus, pectus carinatum, curly hair, hyperkeratosis, wrinkled palms and soles, hyperpigmentation, hypertropic cardiomyopathy, mild intellectual disability, visual field contraction, optic atrophy | 30368668 |
c.1660G>C (p.Ala554Pro) | Heterozygous | Paternal | Proband: relative macrocephaly, typical NS facial features, short neck, webbing of neck, cubitus valgus, curly hair, hyperelastic skin, hyperkeratosis, wrinkled palms and soles, hyperpigmentation, naevus, hypertropic cardiomyopathy, atrial septal defect, intellectual disability | 30368668 |
c.742G>A (p.Gly248Arg) | Heterozygous | De novo | Proband: cryptorchidism, choroid plexus cyst, mild pulmonary supravalvular stenosis, typical NS facial features, curly hair | 31533111 |
c.2074T>A (p.Phe692Leu) | Homozygous | Maternal/paternal | Proband: short stature, mild pulmonary supravalvular stenosis, Von Willebrand disease, cryptorchidism, orchidopexy, typical NS facial features, webbed neck | 31533111 |
c.730T>C (p.Ser244Pro) | Heterozygous | Maternal | Proband: Chiari malformation type I, mild dorsal syringomyelia, hemangioma in the posterior cervical region, mastocytosis, high arched palate, crowded teeth, typical NS facial features, height lower end of the normal range, webbed neck Mother: mild facial features, curly hair, height lower end of the normal range, pectum excavatum, webbed neck | 31533111 |