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Table 2 Incidental genetic findings and outcomes identified across four study sites conducting genomic testing for pediatric patients

From: Return of non-ACMG recommended incidental genetic findings to pediatric patients: considerations and opportunities from experiences in genomic sequencing

Patient ID

Study site

Age

Sex

Indication for testing

Gene

Variant effect

Disease association (mode of inheritance)

Variant origin

Disease age of onset

Outcome/challenges

1

SouthSeq

14 days

M

FTT, renal cyst, developmental hip dysplasia, PFO, retrognathia, possible intracardiac tumors

ABCD1

p.Arg617Cys

Adrenoleukodystrophy (XLR)

Mat

Childhood to adulthood

Post RoR testing revealed increased VLCFA levels suggestive of adrenoleukodystrophy diagnosis; empowered family and clinicians for additional testing/clinical management

2

COAGS

4 years

M

Dysmorphic features, pseudoform cleft lip, coloboma

ANLN

p.Arg431Cys

Focal segmental glomerulosclerosis (AD)

ND

Childhood to adulthood

Referred to nephrogenetics clinic for further evaluation. Appointment has not yet occurred

3

COAGS

3 years

F

Hydrocephalus, VSD, cleft palate, DD

ATM

p.Val2716Ala

Breast cancer susceptibility (AD); Ataxia-telangiectasia (AR)

ND

Adulthood

Mother requested appointment for cancer genetic counseling and testing, as there is a family history of a maternal grandmother with breast cancer in her 40s. Mother did not keep the appointment and attempt to reschedule were unsuccessful

4

COAGS

8 years

M

Hirschprung disease, ID, obesity

ATM

p.Lys468fs

Breast cancer susceptibility (AD); Ataxia-telangiectasia (AR)

ND

Adulthood

At RoR discussed NCCN guidelines for screening in adulthood. Offered maternal testing for the variant (father not available), but mother declined. There is no family history of cancer in either side of family

5

KidsCanSeq

8 years

M

Medulloblastoma

ATM

p.Asp2959fs

Breast cancer susceptibility (AD); Ataxia-telangiectasia (AR)

Pat

Adulthood

Returned as a primary finding due to nature of study design (see the “Methods” section); Tumor type has no known association with ATM. Given that there was no paternal family history of cancer, no screening was initiated for proband

6

SouthSeq

19 days

M

VACTERL-related features

CACNA1A

p.Arg1545Ter

Episodic ataxia (AD); Epileptic encephalopathy (AD)

Pata

Childhood to adulthood; Birth or early infancy

Post RoR revealed father exhibited symptoms that overlap features reported for CACNA1A- and PMP22-related disorders; Father declined referral to neurology

6

SouthSeq

19 days

M

VACTERL-related features

PMP22, others

17p12 deletion

Hereditary neuropathy (AD)

Pata

Childhood to adolescence

--

7

COAGS

5 months

F

Failure to thrive, macroglossia, central and obstructive apnea

CHEK2

p.Thr367fs

Cancer predisposition (AD)

ND

Adulthood

Mother requested testing for the CHEK2 variant and is negative. Father later reported additional cancer family history that was not initially disclosed at first visit or at initial RoR. He met with genetic counseling, ordered commercial CHEK2 testing, but later canceled the order due to out-of-pocket cost. He was then provided with information about low/no-cost commercial testing, but it is unclear if he completed testing

8

P3EGS

Prenatal

F

Fetal heart defect

CHEK2

p.Arg137Ter

Cancer predisposition (AD)

Mat

Adulthood

Mother referred to genetics; lost to follow up

9

COAGS

4 years

F

DD, esotropia, periventricular heterotopia

SLC3A1

c.1500+1G>T

Cystinuria (AD, AR)

ND

Childhood to adulthood

Discussed signs and symptoms of the condition at results and will clinically monitor; No family history of symptoms

10

P3EGS

14 months

F

Tracheoesophageal fistula, tethered cord, hypoplastic thumb, microcephaly, small size

COL4A5

p.Gly1116Val

Alport syndrome (XLD)

Pata

Infancy to adulthood

This variant was not originally formally reported out to the family due to the incidental nature of the finding. However, it was later determined that the father of the proband has a personal history of Alport syndrome and therefore the study requested that the lab look at Alport-associated genes. It was determined that the proband harbored a pathogenic variant in COL4A5 associated with X-linked dominant Alport syndrome. This result was then returned to the family and it was recommended that the proband be followed up with nephrology.

11

SouthSeq

3 days

M

Subcutaneous mass suggestive of lipoma, lymph node or resolving hematoma; maternal family history of having "bumps all over the skin, sometimes painful"

FLCN

17p11.2 deletion

Birt-Hogg-Dube (BHD) syndrome (AD)

Pat

Adulthood

Originally returned as a primary finding; post RoR, event was clinically validated and determined to be paternally inherited; ultimately classified as an incidental finding. Clinicians are deferring BHD management/surveillance until adulthood

12

P3EGS

17 months

F

Bilateral thumb hypoplasia with family history of Cavanagh syndrome

HFE

p.Cys282Tyr

Hemochromatosis (AR)

Biparental

Adulthood

Parents had difficulty understanding the implications of this unanticipated result and the timing as any effects due to pathogenic variants in HFE are not anticipated until adult life

12

P3EGS

17 months

F

Bilateral thumb hypoplasia with family history of Cavanagh syndrome

HFE

p.His63Asp

Hemochromatosis (AR)

Adulthood

--

13

COAGS

5 years

M

DD, epilepsy, autism

HMBS

p.Arg116Trp

Acute Intermittent Porphyria (AD)

Mata

Adolescence to adulthood

Obtained screening urine studies for the patient (pending at specialty lab). Mother requested genetic testing and is positive and referred to GI specialist in porphyria. At RoR discussion, mother endorsed symptoms of porphyria and years of GI scopes/studies which have been non-diagnostic

14

COAGS

15 years

M

Tremor, autism, hypernasal speech, congenital heart defect

HOXB13

p.Gly84Glu

Hereditary prostate cancer (AD)

ND

Adulthood

Mother reported that she shared copies of the child's report with both maternal and paternal relatives as it is unknown if/from whom the variant was inherited

15

P3EGS

3 years

F

ID/NDD

MC4R

p.Ile269Asn

Obesity (AD)

Pata

Infancy

Paternal family members exhibit obesity

16

COAGS

6 years

M

DD, failure to thrive, dysmorphic features

MFN2

p.Arg707Trp

Charcot-Marie-Tooth disease (AD, AR)

ND

Childhood to adulthood; Infancy/early childhood

Discussed signs and symptoms of the condition at RoR and will clinically monitor. No family history of symptoms

17

COAGS

18 years

F

DD/NDD, short stature, hirsutism, dsymorphic features

MITF

p.Glu425Lys

Susceptibility to cutaneous malignant melanoma (AD)

ND

Adulthood

Discussed surveillance and skin protection at RoR. No family history of melanoma

18

SouthSeq

25 days

F

IUGR, congenital microcephaly, congenital hearing loss, cardiomyopathy, thrombocytopenia, intraabdominal abcess, mid jejunal necrosis/perforation

PRRT2

p.Arg217Pfs

Episodic kinesigenic dyskinesia (AD); Benign familial infantile seizures (AD)

ND

Childhood to adolescence

Donor egg; parents did not want findings placed in the EHR but encouraged to share with infant's health care providers; Patient is followed in Neurodevelopmental Clinic and Early Steps

19

SouthSeq

24 days

M

Cardiac and urogenital anomalies

SCN4A

p.Ile1455Thr

Paramyotonia congenita (AD)

Pata

Infancy to early childhood

Post RoR, revealed father exhibited symptoms that overlap features reported for SCN4A-related condition and was excited to learn of why he has stiffness regularly

20

COAGS

9 months

M

Dysmorphic features, dysphagia, hip dysplasia

SLC6A5

p.Cys3Ter

Hyperekplexia (AD, AR)

ND

Newborn to infancy

Family reported no history of symptoms of the condition

21

COAGS

5 years

M

Cutis verticis gyrata, bifid uvula, autism-like behaviors

SLC7A9

p.Gly105Arg

Cystinuria (AD, AR)

ND

Childhood to adulthood

Post RoR, reported family history of multiple people with kidney stones. Alerted pediatrician to monitor if symptoms arise

  1. All variants are heterozygous with exception of the missense in ABCD1 (hemizygous)
  2. M male, F female, VACTERL vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities, ID/NDD intellectual disability, neurodevelopmental delay, VSD ventricular septal defect, FTT failure to thrive, AD autosomal dominant, AR autosomal recessive, XLD X-linked dominant, XLR X-linked recessive, ND not determined, Mat maternal, Pat paternal, RoR return of results
  3. aFamily history of disorder; some not revealed until after RoR