Beyond Single Diagnosis: Exploring Multidiagnostic Realities in Pediatric Patients through Genome Sequencing

Table 2

Genotype-phenotype correlation in cases positive for definitive multiple genetic diagnoses.

Study ID	Submitted clinical presentation	Prior genetic testing	Molecular mechanism	Dx/related features	Overlapping/distinctive
PKIG00155	3-year-old female with short stature, brachydactyly, macrocephaly, progressive lumbar kyphosis, very short extremities, shortening of tubular bones of both extremities appears with widening and lower lumbar lordosis, febrile seizures, concern for achondroplasia and hypochondroplasia	External karyotype and panel testing: nondiagnostic	COL2A1 c.2257G>A p.(Gly753Ser), heterozygous, pathogenic	COL2A1-related skeletal dysplasia/short stature, brachydactyly, macrocephaly, progressive lumbar kyphosis, very short extremities, shortening of tubular bones of both extremities appears with widening and lower lumbar lordosis	Distinctive
			PCDH19 c.2571_2572delGC p.?, heterozygous, pathogenic	Developmental and epileptic encephalopathy 9/febrile seizures
PKIG00180	1-month-old female with nonimmune fetal hydrops, dysmorphic facial features (low-set ears and upslanting palpebral fissure) concerning for Down syndrome, skeletal dysplasia, Noonan syndrome, severe edema/ascites, hypotension, hypothyroidism, elevated amino acid, SCID, large perimembranous VSD, persistent pulmonary hypertension of newborn, single palmar crease on left hand, rhizomelic shortening of upper and lower extremities, polyhydramnios, premature birth	None	33.7 Mb dup of 21q11.2q22.3, pathogenic	Down syndrome/dysmorphic facial features, severe edema/ascites, hypotension, hypothyroidism, large perimembranous VSD, single palmar crease on left hand, rhizomelic shortening of upper and lower extremities	Distinctive
			GLA c.679C>T p.(Arg227Ter), heterozygous, pathogenic	Fabry disease, cardiac variant/too early to manifest
PKIG00282 [7]	1.5-month-old male with sudden death, IUGR, small for gestational age, congenital cardiac malformation, right ventricular hypertrophy, bilateral peripheral pulmonary artery stenosis, patent foramen ovale, thickened aortic valve, aortic arch hypoplasia, arrhythmia, hypertension, Williams syndrome, hypoglycemia, hepatomegaly, dysmorphic facial features, inborn error of metabolism	External CMA: 7q11.23 deletion reported	1.5 Mb del of 7q11.23, pathogenic	Williams-Beuren syndrome/IUGR, small for gestational age, congenital cardiac malformation, bilateral peripheral pulmonary artery stenosis, patent foramen ovale, thickened aortic valve, aortic arch hypoplasia, dysmorphic facial features	Distinctive
			1.04 Mb dup of 16p13.11, likely pathogenic	16p13.11 microduplication syndrome/right ventricular hypertrophy, arrhythmia, hypertension
PKIG00374 [7]	17-year-old male with bilateral optic nerve colobomata, bifid uvula, seizures, focal epilepsy onset at 1 year old, bilateral ptosis, congenital nystagmus, myopia, microphthalmia, cryptorchidism, developmental delay, nonverbal, severe speech and language delay, intellectual disability, legal blindness, palmoplantar hyperkeratosis, dolichocephaly, long face, low-set ears, tapering fingers, hyperpigmentation on lower right leg, bilateral sensorineural hearing loss	External karyotype and panel testing: nondiagnostic; External CMA: 9q22.32 duplication reported	PACS1 c.607C>T p.(Arg203Trp), heterozygous, pathogenic	Schuurs-Hoeijmakers syndrome/focal epilepsy, bilateral ptosis, congenital nystagmus, myopia, developmental delay, nonverbal, severe speech and language delay, intellectual disability, low-set ears	Distinctive
			GJB2 c.101T>C p.(Met34Thr), heterozygous, pathogenic	GJB2-related deafness/bilateral sensorineural hearing loss, palmoplantar hyperkeratosis
			GJB2 c.109G>A p.(Val37Ile), heterozygous, pathogenic
PKIG00405	6-year-old female with dysgenesis of corpus callosum, muscular hypotonia, microcephaly, delayed motor development, delayed language development, intellectual disability, attention deficit disorder, elevated liver enzymes, coloboma, microphthalmia, strabismus, visual impairment, hypodontia, dysmorphic facial features, hypotelorism, upslanting palpebral fissure, low-set protruding posterior rotated ears, midface hypoplasia, prominent everted upper lips, small chin, small nails, clinodactyly, overlapping toes, failure to thrive, IUGR, oligohydramnios. Clinical features manifested in infancy	External karyotype: nondiagnostic	THOC6 c.810+1G>A p.?, homozygous, likely pathogenic	Beaulieu-Boycott-Innes syndrome/microcephaly, delayed motor development, delayed language development, intellectual disability, dysmorphic facial features, upslanting palpebral fissure, prominent everted upper lips	Distinctive, overlapping feature: visual impairment
			ABCA4 c.5882G>A p.(Gly1961Glu), homozygous, pathogenic with reduced penetrance	ABCA4-related ocular disorders; retinitis pigmentosa 1/visual impairment
			RP1 c.5248G>T p.(Glu1750Ter), homozygous, likely pathogenic
PKIG00596	5-year-old male born in a consanguineous couple presented with delayed motor development, delayed language development, developmental delay, hypertension, microcornea, ptosis, sclerocornea, bilateral symmetrical globi pallidi hypodensities, hyperkalemia, poor growth	External panel testing: MMUT variant reported	MMUT c.2200C>T p.(Gln734Ter), homozygous, pathogenic	Methylmalonic aciduria, mut(0) type/delayed motor development, delayed language development, developmental delay, bilateral symmetrical globi pallidi hypodensities, poor growth	Distinctive
			KERA c.1026del p.?, homozygous, likely pathogenic	Cornea plana 2/microcornea, sclerocornea
PKIG01041	5-year-old female with developmental delay, congenital hypotonia, right side weakness	None	CUL3 c.264+1G>C p.?, heterozygous, likely pathogenic	Neurodevelopmental disorder with or without autism or seizures/developmental delay	Overlapping feature: developmental delay
			1.5 Mb dup of 22q11.21, pathogenic	Chromosome 22q11.2 duplication syndrome/developmental delay, congenital hypotonia, right side weakness
			836.3 kb dup of 22q11.21, pathogenic
PKIG01194	1-week-old female with craniosynostosis, scleroderma, visual impairment, multiple joint contractures, syndactyly, talipes equinovarus, defect of ventricular septum, thirteen pairs of ribs, early ossification of femoral heads, narrow chest, narrow palpebral fissure, corneal opacities, macroglossia, ear anomalies, micrognathia	None	3.5 Mb del of 2q37.3, pathogenic	Unbalanced translocation involving chromosomes 2q and 9q/syndactyly, talipes equinovarus, thirteen pairs of ribs, early ossification of femoral heads, narrow chest, narrow palpebral fissure, macroglossia, ear anomalies, micrognathia, craniosynostosis	Distinctive
			17.7 Mb dup of 9q33.2q34.3, pathogenic
			1.3 Mb dup of 16p13.11, likely pathogenic	Chromosome 16p13.11 microduplication syndrome/too early to manifest
PKIG01276	5-year-old male with Charcot-Marie-Tooth disease, developmental delay starting at 9 month old, intellectual disability, femoral congenital anteversion, craniosynostosis, facial hypotonia, broad and flat nasal bridge, telecanthus	External CMA: 17p12 duplication and 18q12.2 deletion (likely benign) reported	1.4 Mb dup of 17p12, pathogenic	Charcot Marie-Tooth disease Type 1A/Charcot-Marie-Tooth disease	Distinctive, overlapping features: developmental delay, intellectual disability
			POGZ c.2324_2325insTT p.?, heterozygous, likely pathogenic	White-Sutton syndrome/developmental delay, intellectual disability, facial hypotonia, broad and flat nasal bridge, telecanthus; 15q11.2 deletion syndrome/developmental delay, intellectual disability
			529.4 kb del of 15q11.2, pathogenic
PKIG01425	8-year-old male with short stature, pulmonary valve stenosis, supravalvular pulmonic stenosis, glycogen storage disease, eosinophilic esophagitis. Clinical features manifested around 6 weeks	External G6PC sequencing: G6PC variant reported	PTPN11 c.1492C>T p.(Arg498Trp), heterozygous, pathogenic	Noonan spectrum disorder/short stature, pulmonary valve stenosis, supravalvular pulmonic stenosis	Distinctive
			G6PC c.247C>T p.(Arg83Cys), homozygous, pathogenic	Glycogen storage disease Ia/short stature, glycogen storage disease
PKIG01849	2-month-old male with microcephaly, hypertonia, small for gestational age, slow growth, IUGR, failure to thrive, underdeveloped inferior vermis, cryptorchidism, low-set posteriorly rotated ears, poor feeding, gastroesophageal reflux, aortic root dilation, phenylketonuria	External CMA: nondiagnostic	KAT6A c.3385C>T p.(Arg1129Ter), heterozygous, pathogenic	Arboleda-Tham syndrome/microcephaly, small for gestational age, slow growth, IUGR, failure to thrive, low-set posteriorly rotated ears, poor feeding, gastroesophageal reflux	Distinctive
			PAH c.527G>T p.(Arg176Leu), heterozygous, pathogenic	Phenylketonuria/microcephaly, phenylketonuria
			PAH c.898G>T p.(Ala300Ser), heterozygous, pathogenic
PKIG02092	2-year-old male with failure to thrive, gross motor developmental delay, speech delay, global developmental delay, congenital hypotonia, congenital nystagmus, esotropia, hypospadias, cryptorchidism, feeding difficulties, dysphagia, neurofibromatosis type 1. Clinical features manifested at 8 months	NF1 and SPREAD1 sequencing: NF1 variant reported	11.9 Mb dup of 20q13.2q13.33, pathogenic	20q trisomy/gross motor developmental delay, speech delay, global developmental delay	Overlapping feature: developmental delay
			11.9 Mb dup of 13q11q12.3, pathogenic	13q trisomy/failure to thrive, gross motor developmental delay, speech delay, global developmental delay
PKIG02101	1-week-old male with arrhythmia, respiratory failure, possible lactic acidosis, seizures, apnea, neonatal jaundice, hyperkalemia, hypomagnesemia, transitory hyperammonemia, deformity of feet, anuria, oliguria, abnormal kidney function, abnormal phosphorus metabolism, abnormal liver function, hypotension	None	600.5 kb del of Xp11.4, hemizygous, pathogenic	Ornithine transcarbamylase deficiency/seizures, apnea, hyperammonemia	Distinctive
			RORB c.286G>T p.(Glu96Ter), heterozygous, likely pathogenic	Susceptibility to idiopathic generalized epilepsy 15/seizures
PKIG00063	11-year-old male presented seizure with clonic movement, oligohydramnios, IUGR, microphthalmia, bilateral congenital cataract, nonpalpable testes, multiple VSD with Gerbode defect, enlarged epiglottis, laryngomalacia, tracheomalacia, failure to thrive, respiratory distress, asthma, adrenal insufficiency, hypothyroidism, gonadotropin deficiency, microphallus, sleep apnea, sensorineural hearing loss, diabetic ketoacidosis, left hemiparesis, nephrotic syndrome, development delay, hypotonia, congenital heart defects, hyperglycemia. Clinical features present at birth	External karyotype: trisomy 21 reported; External CMA: trisomy 21, 2q11.1q12.1 duplication, and 5p15.33q35.3 AOH reported	ERCC8 c.613G>C p.(Ala205Pro), homozygous, likely pathogenic	Cockayne syndrome, type A/seizure, IUGR, cataract, hypogonadism, sensorineural hearing loss, left hemiparesis, hypotonia	Overlapping features: seizure, hearing loss, hypotonia
			8.8 Mb dup of 2q11.1q12.1, likely pathogenic	Sensorineural hearing loss, seizure/VSD, congenital heart defects, seizure, hypotonia, hypothyroidism, gonadotropin deficiency
			Trisomy 21, pathogenic
PKIG00099	11-year-old male with autism, Asperger’s, ADHD, abnormal myelination, frontal lobe demyelination, ataxia, visual impairment, blurry vision, eye pain, abnormal VEP, bilateral sensorineural hearing loss, hyporeflexia, neuropathy, clinical improvement (less ataxia, return to reflexes) with high-dose riboflavin (B2) supplementation, constipation. Clinical features manifested at 10 years	External aCGH/SNP analysis: XXY aneuploidy reported	ACOX1 c.710A>G p.(Asn237Ser), heterozygous, likely pathogenic	Mitchell syndrome/abnormal myelination, frontal lobe demyelination, ataxia, hearing loss, hyporeflexia, neuropathy	Distinctive
			XYY aneuploidy pathogenic	Jacobs syndrome/ADHD

2nd mechanism and 2nd Dx include two molecular diagnoses with overlapping clinical presentations. Abbreviations: Dx: diagnosis; SCID: severe combined immunodeficiency; VSD: ventricular septal defect; IUGR: intrauterine growth restriction; ADHD: attention deficient hyperactivity disorder; VEP: visual evoked potential; CMA: chromosomal microarray; aCGH: array comparative genomic hybridization SNP: single nucleotide polymorphism; VUS: variant of uncertain significance. Note: for comprehensive case-level information, including HPO terms, variant nomenclature, and other details, please refer to Table S4 in the supplement.