Genetic Basis of Congenital Central Hypothyroidism in Children: Expanding the Mutational Spectrum of POU1F1 and ATP6V0A4

Figures & data

Figure 1 Sanger sequencing for validation of the variations detected by the next-generation sequencing platforms. (A) ATP6V0A4 c.1418C>T variant in family members of Individual 1. (B) POU1F1 c.416G>A (p. Arg139Gln) variant in family of Individual 1.

Figure 2 Sanger sequencing for validation of the variations detected by the next-generation sequencing platforms. POU1F1 c.212C>T variant in family members of Individual 2.

Table 1 Evaluation and Classification of the Three Genetic Variants Detected by WES

Gene	Variant (hg19)	Classification	PS2	PM1	PM2	PP3	PP4
			De Novo (Both Maternity and Paternity Confirmed) in a Individual with the Disease and no Family History	Located in Functional Domain	Frequency in Globe Population (and East Asian)	Multiple Lines of Computational Evidence Support a Deleterious Effect on the Gene or Gene Product	Individual’s Phenotype or Family History is Highly Specific for a Disease with a Single Genetic Etiology
POU1F1	NM_000306.4:c.212C>T(p.Ala71Val)	LP	No	POU-specific domain	0 (0)	Yes	Yes
POU1F1	NM_000306.4:c.338G>A(p.Arg113Gln)	LP	Yes	POU-specific domain	0 (0)	Yes	No
ATP6V0A4	ENST00000310018.2:c.1418C>T(p.Ser473Phe)	VUS	No	NA	0 (0)	Yes	No

Notes: Classification and evidence system according to ACMG/AMP variants interpretation guidelines.¹⁵ PS2=De novo (both maternity and paternity confirmed) in a Individual with the disease and no family history. PM1= Located in a mutational hot spot and/or critical and well-established functional domain (eg, active site of an enzyme) without benign variation. PM2=Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes, or Exome Aggregation Consortium. PM3=For recessive disorders, detected in trans with a pathogenic variant. PP3=Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc). PP4=Individual’s phenotype or family history is highly specific for a disease with a single genetic etiology.

Abbreviations: LP, likely pathogenic; VUS, Variants of Uncertain Significance; NA, not applicable.

Figure 3 CMA testing result of Individual 1. A 24 Mb heterozygous deletion (LOH: loss of heterozygosity) in the 2p12.1p13.13 region was detected.

Table 2 Clinical Features, Laboratory results in Seven Individuals

Individual	Sex	Age* (Month)	Weight* (kg) Centile	Length* (cm) Centile	TSH* (mIU/l)	FT3* (pmol/l)	FT4* (pmol/l)	L-T4 (μg/kg/day) Initial/Current	Thyroid Morphology	Reason for Encounter	Development/Age (Year)	Clinical Phenotype
1	Female	12	7.0 (under 3rd)	65 (under 3rd)	6.96	3.06	11.03	2.4/-	Normal	Metabolic acidosis, developmental delay	Short stature /6.3	TCCH
2	Female	13	6.8 (under 3rd)	64 (under 3rd)	2.14	1.79	3.49	4.2/1.5	Normal	Short stature, growth delay, language retardation	Short stature /4.10	PCCH
3	Female	2day	3.65 (75rd-90rd)	50 (50rd-75rd)	7.04	2.47	10.16	4.6/-	Normal	TSH elevation on newborn screening	Normal/10.10	TCCH
4	Female	16	7.2 (under 3rd)	77 (25rd-50rd)	3.26	2.73	11.49	3.5/2.4	Normal	Fever, vomiting	Short stature /4.3	PCCH
5	Female	16	6 (under 3rd)	66 (under 3rd)	3.11	5.33	7.07	2.8/2.1	Normal	Growth delay, cleft palate	Short stature /7.5	PCCH
6	Male	3.5	5.0 (under 3rd)	60 (under 3rd)	3.56	4.3	7.71	3.3/1.2	Normal	Growth delay	Normal /6	TCCH
7	Male	25	8.2 (under 3rd)	69 (under 3rd)	3.93	5.07	11.89	3.0/4.1	Normal	Growth delay	Short stature /8.4	PCCH

Notes: *Age, weight, length, TSH, FT3 and FT4 at diagnosis.

Abbreviations: PCCH, permanent congenital central hypothyroidism; TCCH, transient congenital central hypothyroidism.

Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med. 2015;17(5):405–424. doi:10.1038/gim.2015.30

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